The Enzyme Database

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EC 1.1.99.18     
Accepted name: cellobiose dehydrogenase (acceptor)
Reaction: cellobiose + acceptor = cellobiono-1,5-lactone + reduced acceptor
Other name(s): cellobiose dehydrogenase; cellobiose oxidoreductase; Phanerochaete chrysosporium cellobiose oxidoreductase; CBOR; cellobiose oxidase; cellobiose:oxygen 1-oxidoreductase; CDH; cellobiose:(acceptor) 1-oxidoreductase
Systematic name: cellobiose:acceptor 1-oxidoreductase
Comments: Also acts, more slowly, on cello-oligosaccharides, lactose and D-glucosyl-1,4-β-D-mannose. The enzyme from the white rot fungus Phanerochaete chrysosporium is unusual in having two redoxin domains, one containing a flavin and the other a protoheme group. It transfers reducing equivalents from cellobiose to two types of redox acceptor: two-electron oxidants, including redox dyes, benzoquinones, and molecular oxygen, and one-electron oxidants, including semiquinone species, iron(II) complexes, and the model acceptor cytochrome c [9]. 2,6-Dichloroindophenol can act as acceptor in vitro.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, PDB, CAS registry number: 54576-85-1
References:
1.  Coudray, M.-R., Canebascini, G. and Meier, H. Characterization of a cellobiose dehydrogenase in the cellulolytic fungus porotrichum (Chrysosporium) thermophile. Biochem. J. 203 (1982) 277–284. [PMID: 7103940]
2.  Dekker, R.F.H. Induction and characterization of a cellobiose dehydrogenase produced by a species of Monilia. J. Gen. Microbiol. 120 (1980) 309–316.
3.  Dekker, R.F.H. Cellobiose dehydrogenase produced by Monilia sp. Methods Enzymol. 160 (1988) 454–463.
4.  Habu, N., Samejima, M., Dean, J.F. and Eriksson, K.E. Release of the FAD domain from cellobiose oxidase by proteases from cellulolytic cultures of Phanerochaete chrysosporium. FEBS Lett. 327 (1993) 161–164. [DOI] [PMID: 8392950]
5.  Baminger, U., Subramaniam, S.S., Renganathan, V. and Haltrich, D. Purification and characterization of cellobiose dehydrogenase from the plant pathogen Sclerotium (Athelia) rolfsii. Appl. Environ. Microbiol. 67 (2001) 1766–1774. [DOI] [PMID: 11282631]
6.  Hallberg, B.M., Henriksson, G., Pettersson, G. and Divne, C. Crystal structure of the flavoprotein domain of the extracellular flavocytochrome cellobiose dehydrogenase. J. Mol. Biol. 315 (2002) 421–434. [DOI] [PMID: 11786022]
7.  Ayers, A.R., Ayers, S.B. and Eriksson, K.-E. Cellobiose oxidase, purification and partial characterization of a hemoprotein from Sporotrichum pulverulentum. Eur. J. Biochem. 90 (1978) 171–181. [DOI] [PMID: 710416]
8.  Ayers, A.R. and Eriksson, K.-E. Cellobiose oxidase from Sporotrichum pulverulentum. Methods Enzymol. 89 (1982) 129–135. [PMID: 7144569]
9.  Mason, M.G., Nicholls, P., Divne, C., Hallberg, B.M., Henriksson, G. and Wilson, M.T. The heme domain of cellobiose oxidoreductase: a one-electron reducing system. Biochim. Biophys. Acta 1604 (2003) 47–54. [DOI] [PMID: 12686420]
[EC 1.1.99.18 created 1983, modified 2002 (EC 1.1.5.1 created 1983, incorporated 2002, EC 1.1.3.25 created 1986, incorporated 2005)]
 
 
EC 3.3.2.6     
Accepted name: leukotriene-A4 hydrolase
Reaction: leukotriene A4 + H2O = leukotriene B4
Glossary: leukotriene A4 = (7E,9E,11Z,14Z)-(5S,6S)-5,6-epoxyicosa-7,9,11,14-tetraenoate
leukotriene B4 = (6Z,8E,10E,14Z)-(5S,12R)-5,12-dihydroxyicosa-6,8,10,14-tetraenoate
Other name(s): LTA4 hydrolase; LTA4H; leukotriene A4 hydrolase
Systematic name: (7E,9E,11Z,14Z)-(5S,6S)-5,6-epoxyicosa-7,9,11,14-tetraenoate hydrolase
Comments: This is a bifunctional zinc metalloprotease that displays both epoxide hydrolase and aminopeptidase activities [4,6]. It preferentially cleaves tripeptides at an arginyl bond, with dipeptides and tetrapeptides being poorer substrates [6] (see EC 3.4.11.6, aminopeptidase B). It also converts leukotriene A4 into leukotriene B4, unlike EC 3.3.2.10, soluble epoxide hydrolase, which converts leukotriene A4 into 5,6-dihydroxy-7,9,11,14-icosatetraenoic acid [3,4]. In vertebrates, five epoxide-hydrolase enzymes have been identified to date: EC 3.3.2.6 (leukotriene A4 hydrolase), EC 3.3.2.7 (hepoxilin-epoxide hydrolase), EC 3.3.2.9 (microsomal epoxide hydrolase), EC 3.3.2.10 (soluble epoxide hydrolase) and EC 3.3.2.11 (cholesterol-5,6-oxide hydrolase) [5].
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, PDB, CAS registry number: 90119-07-6
References:
1.  Evans, J.F., Dupuis, P. and Ford-Hutchinson, A.W. Purification and characterisation of leukotriene A4 hydrolase from rat neutrophils. Biochim. Biophys. Acta 840 (1985) 43–50. [DOI] [PMID: 3995081]
2.  Minami, M., Ohno, S., Kawasaki, H., Rådmark, O., Samuelsson, B., Jörnvall, H., Shimizu, T., Seyama, Y. and Suzuki, K. Molecular cloning of a cDNA coding for human leukotriene A4 hydrolase - complete primary structure of an enzyme involved in eicosanoid synthesis. J. Biol. Chem. 262 (1987) 13873–13876. [PMID: 3654641]
3.  Haeggström, J., Meijer, J. and Rådmark, O. Leukotriene A4. Enzymatic conversion into 5,6-dihydroxy-7,9,11,14-eicosatetraenoic acid by mouse liver cytosolic epoxide hydrolase. J. Biol. Chem. 261 (1986) 6332–6337. [PMID: 3009453]
4.  Newman, J.W., Morisseau, C. and Hammock, B.D. Epoxide hydrolases: their roles and interactions with lipid metabolism. Prog. Lipid Res. 44 (2005) 1–51. [DOI] [PMID: 15748653]
5.  Fretland, A.J. and Omiecinski, C.J. Epoxide hydrolases: biochemistry and molecular biology. Chem. Biol. Interact. 129 (2000) 41–59. [DOI] [PMID: 11154734]
6.  Orning, L., Gierse, J.K. and Fitzpatrick, F.A. The bifunctional enzyme leukotriene-A4 hydrolase is an arginine aminopeptidase of high efficiency and specificity. J. Biol. Chem. 269 (1994) 11269. [PMID: 8157657]
7.  Ohishi, N., Izumi, T., Minami, M., Kitamura, S., Seyama, Y., Ohkawa, S., Terao, S., Yotsumoto, H., Takaku, F. and Shimizu, T. Leukotriene A4 hydrolase in the human lung. Inactivation of the enzyme with leukotriene A4 isomers. J. Biol. Chem. 262 (1987) 10200–10205. [PMID: 3038871]
[EC 3.3.2.6 created 1989, modified 2006]
 
 
EC 3.4.11.15     
Accepted name: aminopeptidase Y
Reaction: Preferentially, release of N-terminal lysine
Other name(s): aminopeptidase Co; aminopeptidase (cobalt-activated); lysyl aminopeptidase
Comments: Requires Co2+; inhibited by Zn2+ and Mn2+. An enzyme best known from Saccharomyces cerevisiae that hydrolyses Lys-NHPhNO2 and, more slowly, Arg-NHPhNO2. Type example of peptidase family M28
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, CAS registry number: 114796-97-3
References:
1.  Achstetter, T., Ehmann, C. and Wolf, D.H. Aminopeptidase Co, a new yeast peptidase. Biochem. Biophys. Res. Commun. 109 (1982) 341–347. [DOI] [PMID: 6758786]
2.  Yasuhara, T., Nakai, T. and Ohashi, A. Aminopeptidase Y, a new aminopeptidase from Saccharomyces cerevisiae. Purification, properties, localization, and processing by protease B. J. Biol. Chem. 269 (1994) 13644–13650. [PMID: 8175799]
3.  Nishizawa, M., Yasuhara, T., Nakai, T., Fujiki, Y. and Ohashi, A. Molecular cloning of the aminopeptidase Y gene of Saccharomyces cerevisiae. Sequence analysis and gene disruption of a new aminopeptidase. J. Biol. Chem. 269 (1994) 13651–13655. [PMID: 8175800]
[EC 3.4.11.15 created 1989, modified 1997]
 
 
EC 3.4.14.9     
Accepted name: tripeptidyl-peptidase I
Reaction: Release of an N-terminal tripeptide from a polypeptide, but also has endopeptidase activity.
Other name(s): tripeptidyl aminopeptidase; tripeptidyl peptidase
Comments: A lysosomal enzyme that is active at acidic pH. Deficient in classical late-infantile neuronal ceroid lipofuscinosis brain tissue. Belongs in peptidase family S53. Formerly included in EC 3.4.14.8.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 151662-36-1
References:
1.  Ezaki, J., Tanida, I., Kanehagi, N. and Kominami, E. A lysosomal proteinase, the late infantile neuronal ceroid lipofuscinosis gene (CLN2) product, is essential for degradation of a hydrophobic protein, the subunit c of ATP synthase. J. Neurochem. 72 (1999) 2573–2582. [DOI] [PMID: 10349869]
2.  Rawlings, N.D. and Barrett, A.J. Tripeptidyl-peptidase I is apparently the CLN2 protein absent in classical late-infantile neuronal ceroid lipofuscinosis. Biochim. Biophys. Acta 1429 (1999) 496–500. [DOI] [PMID: 9989235]
3.  Ezaki, J., Takeda-Ezaki, M., Oda, K. and Kominami, E. Characterization of endopeptidase activity of tripeptidyl peptidase-I/CLN2 protein which is deficient in classical late infantile neuronal ceroid lipofuscinosis. Biochem. Biophys. Res. Commun. 268 (2000) 904–908. [DOI] [PMID: 10679303]
4.  Junaid, M.A., Wu, G.X. and Pullarkat, R.K. Purification and characterization of bovine brain lysosomal pepstatin-insensitive proteinase, the gene product deficient in the human late-infantile neuronal ceroid lipofuscinosis. J. Neurochem. 74 (2000) 287–294. [DOI] [PMID: 10617131]
5.  Lin, L., Sohar, I., Lackland, H. and Lobel, P. The human CLN2 protein/tripeptidyl-peptidase I is a serine protease that autoactivates at acidic pH. J. Biol. Chem. 276 (2001) 2249–2255. [DOI] [PMID: 11054422]
[EC 3.4.14.9 created 1992 (part of EC 3.4.14.8 created 1989, incorporated 1992), modified 2000, modified 2001, modified 2003]
 
 
EC 3.4.16.6     
Accepted name: carboxypeptidase D
Reaction: Preferential release of a C-terminal arginine or lysine residue
Other name(s): cereal serine carboxypeptidase II; Saccharomyces cerevisiae KEX1 gene product; carboxypeptidase Kex1; gene KEX1 serine carboxypeptidase; KEX1 carboxypeptidase; KEX1 proteinase; KEX1DELTAp; CPDW-II; serine carboxypeptidase (misleading); Phaseolus proteinase
Comments: A carboxypeptidase with optimum pH 4.5-6.0, inhibited by diisopropyl fluorophosphate, and sensitive to thiol-blocking reagents (reviewed in [1]). In peptidase family S10 (carboxypeptidase C family).
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 153967-26-1
References:
1.  Breddam, K. Serine carboxypeptidases. A review. Carlsberg Res. Commun. 51 (1986) 83–128.
2.  Breddam, K., Sørensen, S.B. and Svendsen, I. Primary structure and enzymatic properties of carboxypeptidase II from wheat bran. Carlsberg Res. Commun. 52 (1987) 297–311.
3.  Dmochowska, A., Dignard, D., Henning, D., Thomas, D.Y. and Bussey, H. Yeast KEX1 gene encodes a putative protease with a carboxypeptidase B-like function involved in killer toxin and α-factor precursor processing. Cell 50 (1987) 573–584. [DOI] [PMID: 3301004]
4.  Liao, D.-I., Breddam, K., Sweet, R.M., Bullock, T. and Remington, S.J. Refined atomic model of wheat serine carboxypeptidase II at 2.2-Å resolution. Biochemistry 31 (1992) 9796–9812. [PMID: 1390755]
[EC 3.4.16.6 created 1972 as EC 3.4.12.1, transferred 1978 to EC 3.4.16.1, part transferred 1993 to EC 3.4.16.6 (EC 3.4.16.3 created 1972 as EC 3.4.12.12, transferred 1978 to EC 3.4.16.3, transferred 1992 to EC 3.4.16.1), (EC 3.4.21.13 created 1972, transferred 1978 to EC 3.4.16.1), modified 2011]
 
 
EC 3.4.18.1     
Accepted name: cathepsin X
Reaction: Release of C-terminal amino acid residues with broad specificity, but lacks action on C-terminal proline. Shows weak endopeptidase activity
Other name(s): cathepsin B2; cysteine-type carboxypeptidase; cathepsin IV; cathepsin Z; acid carboxypeptidase; lysosomal carboxypeptidase B
Comments: Cathepsin X is a lysosomal cysteine peptidase of family C1 (papain family). The pH optimum is dependent on the substrate and is 5.0 for the carboxypeptidase activity. Unstable above pH 7.0. Compound E-64, leupeptin and antipain are inhibitors, but not cystatin C. Cathepsin X is ubiquitously distributed in mammalian tissues. The propeptide is extremely short (38 amino acid residues) and the proenzyme is catalytically active. Human gene locus: 20q13.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, CAS registry number: 37217-21-3
References:
1.  Nägler, D.K., Zhang, R., Tam, W., Sulea, T., Purisima, E.O. and Ménard, R. Human cathepsin X: A cysteine protease with unique carboxypeptidase activity. Biochemistry 38 (1999) 12648–12654. [DOI] [PMID: 10504234]
2.  Nägler, D.K. and Ménard, R. Human cathepsin X: A novel cysteine protease of the papain family with a very short proregion and unique insertions. FEBS Lett. 434 (1998) 135–139. [DOI] [PMID: 9738465]
3.  Santamaría, I. Velasco, G., Pendás, A.M., Fueyo, A. and López-Otín, C. Cathepsin Z, a novel human cysteine proteinase with a short propeptide domain and a unique chromosomal location. J. Biol. Chem. 273 (1998) 16816–16823. [DOI] [PMID: 9642240]
4.  McDonald, J.K. and Ellis, S. On the substrate specificity of cathepsins B1 and B2 including a new fluorogenic substrate for cathepsin B1. Life Sci. 17 (1975) 1269–1276. [PMID: 577]
5.  Otto, K. and Riesenkönig, H. Improved purification of cathepsin B1 and cathepsin B2. Biochim. Biophys. Acta 379 (1975) 462–475. [DOI] [PMID: 1122298]
6.  Ninjoor, V., Taylor, S.L. and Tappel, A.L. Purification and characterization of rat liver lysosomal cathepsin B2. Biochim. Biophys. Acta 370 (1974) 308–321. [DOI] [PMID: 4429705]
[EC 3.4.18.1 created 1981, modified 2000]
 
 
EC 3.4.19.15     
Accepted name: desampylase
Reaction: an N6-[small archaeal modifier protein]-[protein]-L-lysine + H2O = a [protein]-L-lysine + a small archaeal modifier protein
Glossary: SAMP = small archaeal modifier protein
Other name(s): SAMP-protein conjugate cleaving protease; HvJAMM1
Systematic name: N6-[small archaeal modifier protein]-[protein]-L-lysine hydrolase
Comments: The enzyme, characterized from the archaeon Haloferax volcanii, specifically cleaves the ubiquitin-like small modifier proteins SAMP1 and SAMP2 from protein conjugates, hydrolysing the isopeptide bond between a lysine residue of the target protein and the C-terminal glycine of the modifier protein. The enzyme contains Zn2+. cf. EC 3.4.19.12, ubiquitinyl hydrolase 1. In peptidase family M67.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc
References:
1.  Hepowit, N.L., Uthandi, S., Miranda, H.V., Toniutti, M., Prunetti, L., Olivarez, O., De Vera, I.M., Fanucci, G.E., Chen, S. and Maupin-Furlow, J.A. Archaeal JAB1/MPN/MOV34 metalloenzyme (HvJAMM1) cleaves ubiquitin-like small archaeal modifier proteins (SAMPs) from protein-conjugates. Mol. Microbiol. 86 (2012) 971–987. [DOI] [PMID: 22970855]
[EC 3.4.19.15 created 2015 as EC 3.4.24.88, transferred 2016 to EC 3.4.19.15]
 
 
EC 3.4.21.1     
Accepted name: chymotrypsin
Reaction: Preferential cleavage: Tyr┼, Trp┼, Phe┼, Leu┼
Other name(s): chymotrypsins A and B; α-chymar ophth; avazyme; chymar; chymotest; enzeon; quimar; quimotrase; α-chymar; α-chymotrypsin A; α-chymotrypsin
Comments: Chymotrypsin A is formed from cattle and pig chymotrypsinogen A, several iso-forms being produced according to the number of bonds hydrolysed in the precursor. Chymotrypsin B (formerly listed as EC 3.4.4.6), formed from chymotrypsinogen B, is homologous with chymotrypsin A. Enzymes with specificity similar to that of chymotrypsins A and B have been isolated from many species. In peptidase family S1 (trypsin family)
Links to other databases: BRENDA, EXPASY, GTD, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 9004-07-3
References:
1.  Wilcox, P.E. Chymotrypsinogens - chymotrypsins. Methods Enzymol. 19 (1970) 64–108.
2.  Blow, D.M. Structure and mechanism of chymotrypsin. Acc. Chem. Res. 9 (1976) 145–152.
3.  Bauer, C.-A. Active centers of α-chymotrypsin and of Streptomyces griseus proteases 1 and 3. Eur. J. Biochem. 105 (1980) 565–570. [DOI] [PMID: 6768556]
4.  Polgár, L. Structure and function of serine proteases. In: Neuberger, A. and Brocklehurst, K. (Eds), New Comprehensive Biochemistry: Hydrolytic Enzymes, vol. 16, Elsevier, Amsterdam, 1987, pp. 159–200.
5.  Tomita, N., Izumoto, Y., Horii, A., Doi, S., Yokouchi, H., Ogawa, M., Mori, T. and Matsubara, K. Molecular cloning and nucleotide sequence of human pancreatic prechymotrypsinogen cDNA. Biochem. Biophys. Res. Commun. 158 (1989) 569–575. [DOI] [PMID: 2917002]
[EC 3.4.21.1 created 1961 as EC 3.4.4.5 and EC 3.4.4.6, transferred 1972 to EC 3.4.21.1]
 
 
EC 3.4.21.3     
Accepted name: metridin
Reaction: Preferential cleavage: Tyr┼, Phe┼, Leu┼
little action on Trp-┼
Other name(s): Metridium proteinase A; sea anemone protease A; sea anemone proteinase A
Comments: Digestive enzyme from the sea anemone Metridium senile.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, CAS registry number: 37288-75-8
References:
1.  Gibson, D. and Dixon, G.H. Chymotrypsin-like proteases from the sea anemone, Metridium senile. Nature 222 (1969) 753–756. [PMID: 4389140]
2.  Stevenson, K.J., Gibson, D. and Dixon, G.H. Amino acid analyses of chymotrysin-like proteases from the sea anemone (Metridium senile). Can. J. Biochem. 52 (1974) 93–100. [PMID: 4150616]
[EC 3.4.21.3 created 1972]
 
 
EC 3.4.21.4     
Accepted name: trypsin
Reaction: Preferential cleavage: Arg┼, Lys┼
Other name(s): α-trypsin; β-trypsin; cocoonase; parenzyme; parenzymol; tryptar; trypure; pseudotrypsin; tryptase; tripcellim; sperm receptor hydrolase
Comments: The single polypeptide chain cattle β-trypsin is formed from trypsinogen by cleavage of one peptide bond. Further peptide bond cleavages produce α and other iso-forms. Isolated as multiple cationic and anionic trypsins [5] from the pancreas of many vertebrates and from lower species including crayfish, insects (cocoonase) and microorganisms (Streptomyces griseus) [3]. Type example of peptidase family S1.
Links to other databases: BRENDA, EXPASY, GTD, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 9002-07-7
References:
1.  Huber, R. and Bode, W. Structural basis of the activation and action of trypsin. Acc. Chem. Res. 11 (1978) 114–122.
2.  Walsh, K.A. Trypsinogens and trypsins of various species. Methods Enzymol. 19 (1970) 41–63.
3.  Read, R.J., Brayer, G.D., Jurásek, L. and James, M.N.G. Critical evaluation of comparative model building of Streptomyces griseus trypsin. Biochemistry 23 (1984) 6570–6575. [PMID: 6442164]
4.  Fiedler, F. Effects of secondary interactions on the kinetics of peptide and peptide ester hydrolysis by tissue kallikrein and trypsin. Eur. J. Biochem. 163 (1987) 303–312. [DOI] [PMID: 3643848]
5.  Fletcher, T.S., Alhadeff, M., Craik, C.S. and Largman, C. Isolation and characterization of a cDNA encoding rat cationic trypsinogen. Biochemistry 26 (1987) 3081–3086. [PMID: 3112218]
6.  Polgár, L. Structure and function of serine proteases. In: Neuberger, A. and Brocklehurst, K. (Eds), New Comprehensive Biochemistry: Hydrolytic Enzymes, vol. 16, Elsevier, Amsterdam, 1987, pp. 159–200.
7.  Tani, T., Kawashima, I., Mita, K. and Takiguchi, Y. Nucleotide sequence of the human pancreatic trypsinogen III cDNA. Nucleic Acids Res. 18 (1990) 1631. [DOI] [PMID: 2326201]
[EC 3.4.21.4 created 1961 as EC 3.4.4.4, transferred 1972 to EC 3.4.21.4]
 
 
EC 3.4.21.5     
Accepted name: thrombin
Reaction: Selective cleavage of Arg┼Gly bonds in fibrinogen to form fibrin and release fibrinopeptides A and B
Other name(s): fibrinogenase; thrombase; thrombofort; topical; thrombin-C; tropostasin; activated blood-coagulation factor II; blood-coagulation factor IIa; factor IIa; E thrombin; β-thrombin; γ-thrombin
Comments: Formed from prothrombin. More selective than trypsin and plasmin. In peptidase family S1 (trypsin family).
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 9002-04-4
References:
1.  Baughman, D.J. Thrombin assay. Methods Enzymol. 19 (1970) 145–157.
2.  Magnusson, S. Bovine prothrombin and thrombin. Methods Enzymol. 19 (1970) 157–184.
3.  Miller, K.D. Horse prothrombin. Methods Enzymol. 19 (1970) 140–145.
4.  Lundblad, R.L., Kingdon, H.S. and Mann, K.G. Thrombin. Methods Enzymol. 45 (1976) 156–176. [DOI] [PMID: 1011989]
5.  Mann, K.G. Prothrombin. Methods Enzymol. 45 (1976) 123–156. [DOI] [PMID: 1011988]
6.  Davie, E.W., Fujikawa, K., Kurachi, K. and Kisiel, W. The role of serine proteases in the blood coagulation cascade. Adv. Enzymol. 48 (1979) 277–318. [PMID: 367103]
7.  Cho, K., Tanaka, T., Cook, R.R., Kisiel, W., Fujikawa, K., Kurachi, K. and Powers, J.C. Active-site mapping of bovine and human blood coagulation serine proteases using synthetic peptide 4-nitroanilide and thio ester substrates. Biochemistry 23 (1984) 644–650. [PMID: 6370301]
8.  MacGillivray, R.T.A. and Davie, E.W. Characterization of bovine prothrombin mRNA and its translation product. Biochemistry 23 (1984) 1626–1634. [PMID: 6326805]
[EC 3.4.21.5 created 1961 as EC 3.4.4.13, transferred 1972 to EC 3.4.21.5]
 
 
EC 3.4.21.6     
Accepted name: coagulation factor Xa
Reaction: Selective cleavage of Arg┼Thr and then Arg┼Ile bonds in prothrombin to form thrombin
Other name(s): thrombokinase; prothrombase; prothrombinase; activated blood-coagulation factor X; autoprothrombin C; thromboplastin; plasma thromboplastin; factor Xa; activated Stuart-Prower factor; activated factor X
Comments: A blood coagulation factor formed from the proenzyme factor X by limited proteolysis. Factor X is a glycoprotein composed of a heavy chain and a light chain, which are generated from a precursor protein by the excision of the tripeptide RKR and held together by one or more disulfide bonds. The activated factor Xa converts prothrombin to thrombin in the presence of factor Va, Ca2+ and phospholipids. Scutelarin (EC 3.4.21.60) has similar specificity, but does not require factor Va.
Links to other databases: BRENDA, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 9002-05-5
References:
1.  Fujikawa, K. and Davie, E.W. Bovine factor X (Stuart factor). Methods Enzymol. 45 (1976) 89–95. [DOI] [PMID: 1012041]
2.  Jesty, J. and Nemerson, Y. The activation of bovine coagulation factor X. Methods Enzymol. 45 (1976) 95–107. [DOI] [PMID: 1012042]
3.  Davie, E.W., Fujikawa, K., Kurachi, K. and Kisiel, W. The role of serine proteases in the blood coagulation cascade. Adv. Enzymol. 48 (1979) 277–318. [PMID: 367103]
4.  Jackson, C.M. and Nemerson, Y. Blood coagulation. Annu. Rev. Biochem. 49 (1980) 765–811. [DOI] [PMID: 6996572]
5.  McMullen, B.A., Fujikawa, K., Kisiel, W., Sasagawa, T., Howald, W.N., Kwa, E.Y. and Weinstein, B. Complete amino acid sequence of the light chain of human blood coagulation factor X: evidence for identification of residue 63 as β-hydroxyaspartic acid. Biochemistry 22 (1983) 2875–2884. [PMID: 6871167]
6.  Cho, K., Tanaka, T., Cook, R.R., Kisiel, W., Fujikawa, K., Kurachi, K. and Powers, J.C. Active-site mapping of bovine and human blood coagulation serine proteases using synthetic peptide 4-nitroanilide and thio ester substrates. Biochemistry 23 (1984) 644–650. [PMID: 6370301]
[EC 3.4.21.6 created 1972, modified 2011]
 
 
EC 3.4.21.10     
Accepted name: acrosin
Reaction: Preferential cleavage: Arg┼, Lys┼
Other name(s): acrosomal proteinase; acrozonase; α-acrosin; β-acrosin; upsilon-acrosin; acrosomal protease; acrosin amidase
Comments: Occurs in spermatozoa; formed from proacrosin by limited proteolysis. Inhibited by naturally occurring trypsin inhibitors. In peptidase family S1 (trypsin family)
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 9068-57-9
References:
1.  Müller-Esterl, W. and Fritz, H. Sperm acrosin. Methods Enzymol. 80 (1981) 621–632. [PMID: 7043204]
2.  Skoog, M.T., Mehdi, S., Wiseman, J.S. and Bey, P. The specificity of two proteinases that cleave adjacent to arginine, C 1 esterase and acrosin, for peptide p-nitroanilide substrates. Biochim. Biophys. Acta 996 (1989) 89–94. [DOI] [PMID: 2500154]
3.  Keime, S., Adham, I.M. and Engel, W. Nucleotide sequence and exon-intron organisation of the human proacrosin gene. Eur. J. Biochem. 190 (1990) 195–200. [DOI] [PMID: 2114285]
[EC 3.4.21.10 created 1972]
 
 
EC 3.4.21.12     
Accepted name: α-lytic endopeptidase
Reaction: Preferential cleavage: Ala┼, Val┼ in bacterial cell walls, elastin and other proteins
Other name(s): myxobacter α-lytic proteinase; α-lytic proteinase; α-lytic protease; Mycobacterium sorangium α-lytic proteinase; Myxobacter 495 α-lytic proteinase; α-lytic proteinase; Myxobacter α-lytic proteinase; Mycobacterium sorangium α-lytic proteinase
Comments: From the myxobacterium Lysobacter enzymogenes. In peptidase family S1 (trypsin family)
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 37288-76-9
References:
1.  Olson, M.O.J., Nagabushan, N., Dzwiniel, M., Smillie, L.B. and Whitaker, D.R. Primary structure of α-lytic protease: a bacterial homologue of the pancreatic serine proteases. Nature 228 (1970) 438–442. [PMID: 5482494]
2.  Polgár, L. Structure and function of serine proteases. In: Neuberger, A. and Brocklehurst, K. (Eds), New Comprehensive Biochemistry: Hydrolytic Enzymes, vol. 16, Elsevier, Amsterdam, 1987, pp. 159–200.
3.  Epstein, D.M. and Wensink, P.C. The α-lytic protease gene of Lysobacter enzymogenes. The nucleotide sequence predicts a large prepro-peptide with homology to pro-peptides of other chymotrypsin-like enzymes. J. Biol. Chem. 263 (1988) 16586–16590. [PMID: 3053694]
4.  Bone, R., Frank, D., Kettner, C.A. and Agard, D.A. Structural analysis of specificity: α-lytic protease complexes with analogues of reaction intermediates. Biochemistry 28 (1989) 7600–7609. [PMID: 2611204]
[EC 3.4.21.12 created 1972]
 
 
EC 3.4.21.19     
Accepted name: glutamyl endopeptidase
Reaction: Preferential cleavage: Glu┼, Asp┼
Other name(s): V8 proteinase; endoproteinase Glu-C; staphylococcal serine proteinase
Comments: From Staphylococcus aureus strain V8. In appropriate buffer the specificity is restricted to Glu┼. In peptidase family S1 (trypsin family)
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 137010-42-5
References:
1.  Drapeau, G.R. Protease from Staphylococcus aureus. Methods Enzymol. 45 (1976) 469–475. [DOI] [PMID: 1012010]
2.  Drapeau, G.R. The primary structure of staphylococcal protease. Can. J. Biochem. 56 (1978) 534–544. [PMID: 96922]
3.  Carmona, C. and Gray, G.L. Nucleotide sequence of the serine protease gene of Staphylococcus aureus, strain V8. Nucleic Acids Res. 15 (1987) 6757. [DOI] [PMID: 3306605]
[EC 3.4.21.19 created 1978]
 
 
EC 3.4.21.21     
Accepted name: coagulation factor VIIa
Reaction: Selective cleavage of Arg┼Ile bond in factor X to form factor Xa
Other name(s): blood-coagulation factor VIIa; activated blood coagulation factor VII
Comments: Formed from the precursor factor VII. The cattle enzyme is more readily inhibited by diisopropyl fluorophosphate than the human [1]. In peptidase family S1 (trypsin family)
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 65312-43-8
References:
1.  Nemerson, Y. and Esnouf, M.P. Activation of a proteolytic system by a membrane lipoprotein: mechanism of action of tissue factor. Proc. Natl. Acad. Sci. USA 70 (1973) 310–314. [DOI] [PMID: 4510277]
2.  Davie, E.W., Fujikawa, K., Kurachi, K. and Kisiel, W. The role of serine proteases in the blood coagulation cascade. Adv. Enzymol. 48 (1979) 277–318. [PMID: 367103]
3.  Jackson, C.M. and Nemerson, Y. Blood coagulation. Annu. Rev. Biochem. 49 (1980) 765–811. [DOI] [PMID: 6996572]
4.  Broze, G.J., Jr. and Majerus, P.W. Human factor VII. Methods Enzymol. 80 (1981) 228–237.
[EC 3.4.21.21 created 1978]
 
 
EC 3.4.21.22     
Accepted name: coagulation factor IXa
Reaction: Selective cleavage of Arg┼Ile bond in factor X to form factor Xa
Other name(s): activated Christmas factor; blood-coagulation factor IXa; activated blood-coagulation factor IX; autoprothrombin II; blood platelet cofactor II; activated blood coagulation factor XI
Comments: A chymotrypsin homologue, and one of the γ-carboxyglutamic acid-containing blood coagulation factors. The proenzyme factor IX is activated by factor XIa. In peptidase family S1 (trypsin family)
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 37316-87-3
References:
1.  Fujikawa, K. and Davie, E.W. Bovine factor IX (Christmas factor). Methods Enzymol. 45 (1976) 74–83. [DOI] [PMID: 1012029]
2.  Davie, E.W., Fujikawa, K., Kurachi, K. and Kisiel, W. The role of serine proteases in the blood coagulation cascade. Adv. Enzymol. 48 (1979) 277–318. [PMID: 367103]
3.  Link, R.P. and Castellino, F.J. Kinetic comparison of bovine blood coagulation factor IXaα and IXaβ towards bovine factor X. Biochemistry 22 (1983) 4033–4041. [PMID: 6412750]
4.  Cho, K., Tanaka, T., Cook, R.R., Kisiel, W., Fujikawa, K., Kurachi, K. and Powers, J.C. Active-site mapping of bovine and human blood coagulation serine proteases using synthetic peptide 4-nitroanilide and thio ester substrates. Biochemistry 23 (1984) 644–650. [PMID: 6370301]
[EC 3.4.21.22 created 1978]
 
 
EC 3.4.21.25     
Accepted name: cucumisin
Reaction: Hydrolysis of proteins with broad specificity
Other name(s): euphorbain; solanain; hurain; tabernamontanain
Comments: From the sarcocarp of the musk melon (Cucumis melo). In peptidase family S8 (subtilisin family). Other endopeptidases from plants, which are less well characterized but presumably of serine-type, include euphorbain from Euphorbia cerifera [6], solanain from horse-nettle Solanum elaeagnifolium [1], hurain from Hura crepitans [2] and tabernamontanain from Tabernamontana grandiflora [3].
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, CAS registry number: 82062-89-3
References:
1.  Greenberg, D.M. and Winnick, T. Plant proteases. I. Activation-inhibition reactions. J. Biol. Chem. 135 (1940) 761–773.
2.  Jaffé, W.G. Hurain, a new plant protease from Hura crepitans. J. Biol. Chem. 149 (1943) 1–7.
3.  Jaffé, W.G. A new vegetable proteolytic enzyme of the papain class. Rev. Brasil Biol. 3 (1943) 149–157.
4.  Kaneda, M. and Toninaga, N. Isolation and characterization of a proteinase from the sarcocarp of melon fruit. J. Biochem. (Tokyo) 78 (1975) 1287–1296. [PMID: 5423]
5.  Kaneda, M., Ohmine, H., Yonezawa, H. and Tominaga, N. Amino acid sequence around the reactive site of cucumisin from melon fruit. J. Biochem. (Tokyo) 95 (1984) 825–829. [PMID: 6427203]
6.  Lynn, K.R. and Clevette-Radford, N.A. Two proteases from the latex of Elaeophorbia drupifera. Phytochemistry 24 (1985) 2843–2845.
7.  Kaneda, N., Minematsu, Y., Powers, J.C. and Tominaga, N. Specificity of cucumisin in hydrolysis of peptide thiobenzyl esters. Agric. Biol. Chem. 50 (1986) 1075–1076.
[EC 3.4.21.25 created 1978 (EC 3.4.21.56 created 1972 as EC 3.4.99.7 transferred 1989 to EC 3.4.21.56, deleted 1992; EC 3.4.99.9 created 1972 deleted 1992; EC 3.4.99.21 created 1972 deleted 1992; EC 3.4.99.23 created 1972 deleted 1992; all covered by EC 3.4.21.25)]
 
 
EC 3.4.21.27     
Accepted name: coagulation factor XIa
Reaction: Selective cleavage of Arg┼Ala and Arg┼Val bonds in factor IX to form factor IXa
Other name(s): blood-coagulation factor XIa; activated blood-coagulation factor XI; activated plasma thromboplastin antecedent
Comments: In peptidase family S1 (trypsin family), and one of the γ-carboxyglutamic acid-containing blood coagulation factors. The proenzyme factor XI is activated by factor XIIa
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 37203-61-5
References:
1.  Kurachi, K. and Davie, E.W. Human factor XI (plasma thromboplastin antecedent). Methods Enzymol. 80 (1981) 211–220.
2.  Cho, K., Tanaka, T., Cook, R.R., Kisiel, W., Fujikawa, K., Kurachi, K. and Powers, J.C. Active-site mapping of bovine and human blood coagulation serine proteases using synthetic peptide 4-nitroanilide and thio ester substrates. Biochemistry 23 (1984) 644–650. [PMID: 6370301]
3.  Fujikawa, K., Chung, D.W., Hendrickson, L.E. and Davie, E.W. Amino acid sequence of human factor XI, a blood coagulation factor with four tandem repeats that are highly homologous with plasma prekallikrein. Biochemistry 25 (1986) 2417–2424. [PMID: 3636155]
[EC 3.4.21.27 created 1978]
 
 
EC 3.4.21.32     
Accepted name: brachyurin
Reaction: Hydrolysis of proteins, with broad specificity for peptide bonds. Native collagen is cleaved about 75% of the length of the molecule from the N-terminus. Low activity on small molecule substrates of both trypsin and chymotrypsin
Other name(s): Uca pugilator collagenolytic proteinase; crab protease I; crab protease II
Comments: From hepatopancreas of the fiddler crab, Uca pugilator. In peptidase family S1 (trypsin family). Other serine endopeptidases that degrade collagen, but are not listed separately here, include a second endopeptidase from Uca pugilator [4], digestive enzymes from other decapod crustacea [5,6], and an enzyme from the fungus Entomophthora coronata [1].
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 848900-32-3
References:
1.  Hurion, N., Fromentin, H. and Keil, B. Specificity of the collagenolytic enzyme from the fungus Entomophthora coronata: comparison with the bacterial collagenase from Achromobacter iophagus. Arch. Biochem. Biophys. 192 (1979) 438–445. [DOI] [PMID: 219780]
2.  Grant, G.A., Eisen, A.Z. and Bradshaw, R.A. Collagenolytic protease from fiddler crab (Uca pugilator). Methods Enzymol. 80 (1981) 722–734.
3.  Welgus, H.G., Grant, G.A., Jeffrey, J.J. and Eisen, A.Z. Substrate specificity of the collagenolytic serine protease from Uca pugilator: studies with collagenous substrates. Biochemistry 21 (1982) 5183–5189. [PMID: 6756469]
4.  Welgus, H.G. and Grant, G.A. Degradation of collagen substrates by a trypsin-like serine protease form the fiddler crab Uca pugilator. Biochemistry 22 (1983) 2228–2233. [PMID: 6305411]
5.  Klimova, O.A., Borukhov, S.I., Solovyeva, N.I., Balaevskaya, T.O. and Strongin, A.Y. The isolation and properties of collagenolytic proteases from crab hepatopancreas. Biochem. Biophys. Res. Commun. 166 (1990) 1411–1420. [DOI] [PMID: 2154979]
6.  Lu, P.-J., Liu, H.-C. and Tsai, I.-H. The midgut trypsins of shrimp (Penaeus monodon). High efficiency toward native protein substrates including collagens. Biol. Chem. Hoppe-Seyler 371 (1990) 851–859. [PMID: 1963309]
[EC 3.4.21.32 created 1978]
 
 
EC 3.4.21.35     
Accepted name: tissue kallikrein
Reaction: Preferential cleavage of Arg┼ bonds in small molecule substrates. Highly selective action to release kallidin (lysyl-bradykinin) from kininogen involves hydrolysis of Met┼ or Leu┼. The rat enzyme is unusual in liberating bradykinin directly from autologous kininogens by cleavage at two Arg┼ bonds [5]
Other name(s): glandular kallikrein; pancreatic kallikrein; submandibular kallikrein; submaxillary kallikrein; kidney kallikrein; urinary kallikrein; kallikrein; salivary kallikrein; kininogenin; kininogenase; callicrein; glumorin; padreatin; padutin; kallidinogenase; bradykininogenase; depot-padutin; urokallikrein; dilminal D; onokrein P
Comments: Formed from tissue prokallikrein by activation with trypsin. In peptidase family S1 (trypsin family). A large number of tissue kallikrein-related sequences have been reported for rats [16] and mice [7], though fewer seem to exist in other mammals. The few that have been isolated and tested on substrates include mouse γ-renin (EC 3.4.21.54), submandibular proteinase A [2,15], epidermal growth-factor-binding protein, nerve growth factor γ-subunit, rat tonin [3,4,9], submaxillary proteinases A and B [10], T-kininogenase [18], kallikreins k7 and k8 [17] and human prostate-specific antigen (γ-seminoprotein, [6])
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 389069-73-2
References:
1.  Fiedler, F., Fink, E., Tschesche, H. and Fritz, H. Porcine glandular kallikreins. Methods Enzymol. 80 (1981) 493–532. [PMID: 7043199]
2.  Anundi, H., Ronne, H., Peterson, P.A. and Rask, L. Partial amino-acid sequence of the epidermal growth-factor-binding protein. Eur. J. Biochem. 129 (1982) 365–371. [DOI] [PMID: 6295764]
3.  Pesquero, J.L., Boschcov, P., Oliveira, M.C.F. and Paiva, A.C.M. Effect of substrate size on tonin activity. Biochem. Biophys. Res. Commun. 108 (1982) 1441–1446. [DOI] [PMID: 6295383]
4.  Gutkowska, J., Corvol, P., Figueiredo, A.F., Inagami, T., Bouhnik, J. and Genest, J. Kinetic studies of rat renin and tonin on purified rat angiotensinogen. Can. J. Biochem. Cell Biol. 62 (1984) 137–142. [PMID: 6097352]
5.  Kato, H., Enjyoji, K., Miyata, T., Hayashi, I., Oh-Ishi, S. and Iwanaga, S. Demonstration of arginyl-bradykinin moiety in rat HMW kininogen: direct evidence for liberation of bradykinin by rat glandular kallikreins. Biochem. Biophys. Res. Commun. 127 (1985) 289–295. [DOI] [PMID: 3844939]
6.  Akiyama, K., Nakamura, T., Iwanaga, S. and Hara, M. The chymotrypsin-like activity of human prostate-specific antigen, γ-seminoprotein. FEBS Lett. 225 (1987) 168–172. [DOI] [PMID: 3691800]
7.  Evans, B.A., Drinkwater, C.C. and Richards, R.I. Mouse glandular kallikrein genes. Structure and partial sequence analysis of the kallikrein gene locus. J. Biol. Chem. 262 (1987) 8027–8034. [PMID: 3036794]
8.  Fiedler, F. Effects of secondary interactions on the kinetics of peptide and peptide ester hydrolysis by tissue kallikrein and trypsin. Eur. J. Biochem. 163 (1987) 303–312. [DOI] [PMID: 3643848]
9.  Fujinaga, M. and James, M.N.G. Rat submaxillary gland serine protease, tonin. Structure solution and refinement at 1.8 Å resolution. J. Mol. Biol. 195 (1987) 373–396. [DOI] [PMID: 2821276]
10.  Kato, H., Nakanishi, E., Enjyoji, K., Hayashi, I., Oh-ishi, S. and Iwanaga, S. Characterization of serine proteinases isolated from rat submaxillary gland: with special reference to the degradation of rat kininogens by these enzymes. J. Biochem. (Tokyo) 102 (1987) 1389–1404. [PMID: 3482210]
11.  Bailey, G.S. Rat pancreas kallikrein. Methods Enzymol. 163 (1989) 115–128. [PMID: 3237072]
12.  Blaber, M., Isackson, P.J., Marsters, J.C., Jr., Burnier, J.P. and Bradshaw, R.A. Substrate specificities of growth factor associated kallikreins of the mouse submandibular gland. Biochemistry 28 (1988) 7813–7819. [PMID: 2611215]
13.  Chao, J. and Chao, L. Rat urinary kallikrein. Methods Enzymol. 163 (1988) 128–143. [PMID: 3070295]
14.  Geiger, R. and Miska, W. Human tissue kallikrein. Methods Enzymol. 163 (1988) 102–115. [PMID: 2975076]
15.  Bertrand, R., Derancourt, J. and Kassab, R. Selective cleavage at lysine of the 50 kDa-20 kDa connector loop segment of skeletal myosin S-1 by endoproteinase Arg-C. FEBS Lett. 246 (1989) 171–176. [DOI] [PMID: 2523317]
16.  Wines, D.R., Brady, J.M., Pritchett, D.B., Roberts, J.L. and MacDonald, R.J. Organization and expression of the rat kallikrein gene family. J. Biol. Chem. 264 (1989) 7653–7662. [PMID: 2708383]
17.  Elmoujahed, A., Gutman, N., Brillard, M. and Gauthier, F. Substrate specificity of two kallikrein family gene products isolated from the rat submaxillary gland. FEBS Lett. 265 (1990) 137–140. [DOI] [PMID: 2194829]
18.  Xiong, W., Chen, L.-M. and Chao, J. Purification and characterization of a kallikrein-like T-kininogenase. J. Biol. Chem. 265 (1990) 2822–2827. [PMID: 2303430]
[EC 3.4.21.35 created 1965 as EC 3.4.4.21, transferred 1972 to EC 3.4.21.8, part transferred 1981 to EC 3.4.21.35]
 
 
EC 3.4.21.36     
Accepted name: pancreatic elastase
Reaction: Hydrolysis of proteins, including elastin. Preferential cleavage: Ala┼
Other name(s): pancreatopeptidase E; pancreatic elastase I; elastase; elaszym; serine elastase
Comments: Formed by activation of proelastase from mammalian pancreas by trypsin. In peptidase family S1 (trypsin family). Formerly included in EC 3.4.21.11
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 9004-06-2
References:
1.  Shotton, D.M. Elastase. Methods Enzymol. 19 (1970) 113–140.
2.  Harper, J.W., Cook, R.R., Roberts, C.J., McLaughlin, B.J. and Powers, J.C. Active site mapping of the serine proteases human leukocyte elastase, cathepsin G, porcine pancreatic elastase, rat mast cell proteases I and II, bovine chymotrypsin Aα, and Staphylococcus aureus protease V-8 using tripeptide thiobenzyl ester substrates. Biochemistry 23 (1984) 2995–3002. [PMID: 6380580]
3.  Kawashima, I., Tani, T., Shimoda, K. and Takiguchi, Y. Characterization of pancreatic elastase II cDNAs: two elastase II mRNAs are expressed in human pancreas. DNA 6 (1987) 163–172. [DOI] [PMID: 3646943]
4.  Bieth, J.G., Dirrig, S., Jung, M.-L., Boudier, C., Papamichael, E., Sakarellos, C. and Dimicoli, J.-L. Investigation of the active center of rat pancreatic elastase. Biochim. Biophys. Acta 994 (1989) 64–74. [DOI] [PMID: 2909256]
5.  Bode, W., Meyer, E., Jr. and Powers, J.C. Human leukocyte and porcine pancreatic elastase: X-ray crystal structures, mechanism, substrate specificity, and mechanism-based inhibitors. Biochemistry 28 (1989) 1951–1963. [PMID: 2655701]
[EC 3.4.21.36 created 1981 (EC 3.4.4.7 created 1961, transferred 1972 to EC 3.4.21.11 created 1972, part incorporated 1984)]
 
 
EC 3.4.21.37     
Accepted name: leukocyte elastase
Reaction: Hydrolysis of proteins, including elastin. Preferential cleavage Val┼ > Ala┼
Other name(s): lysosomal elastase; neutrophil elastase; polymorphonuclear leukocyte elastase; elastase; elaszym; serine elastase; lysosomal elastase; granulocyte elastase
Comments: Differs from pancreatic elastase in specificity on synthetic substrates and in inhibitor sensitivity. In peptidase family S1 (trypsin family). Formerly included in EC 3.4.21.11
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 9004-06-2
References:
1.  Barrett, A.J. Leukocyte elastase. Methods Enzymol. 80 (1981) 581–588. [PMID: 7043201]
2.  Harper, J.W., Cook, R.R., Roberts, C.J., McLaughlin, B.J. and Powers, J.C. Active site mapping of the serine proteases human leukocyte elastase, cathepsin G, porcine pancreatic elastase, rat mast cell proteases I and II, bovine chymotrypsin Aα, and Staphylococcus aureus protease V-8 using tripeptide thiobenzyl ester substrates. Biochemistry 23 (1984) 2995–3002. [PMID: 6380580]
3.  Stein, R.L., Strimpler, A.M., Hori, H. and Powers, J.C. Catalysis by human leukocyte elastase: mechanistic insights into specificity requirements. Biochemistry 26 (1987) 1301–1305. [PMID: 3646070]
4.  Bode, W., Meyer, E., Jr. and Powers, J.C. Human leukocyte and porcine pancreatic elastase: X-ray crystal structures, mechanism, substrate specificity, and mechanism-based inhibitors. Biochemistry 28 (1989) 1951–1963. [PMID: 2655701]
[EC 3.4.21.37 created 1981 (EC 3.4.4.7 created 1961, transferred 1972 to EC 3.4.21.11 created 1972, part incorporated 1984)]
 
 
EC 3.4.21.38     
Accepted name: coagulation factor XIIa
Reaction: Selective cleavage of Arg┼Ile bonds in factor VII to form factor VIIa and factor XI to form factor XIa
Other name(s): Hageman factor (activated); blood-coagulation factor XIIf; activated β blood-coagulation factor XII; prealbumin activator; Hageman factor β-fragment; Hageman factor fragment HFf; blood-coagulation factor XIIaβ; prekallikrein activator; kallikreinogen activator
Comments: Also activates plasminogen and plasma prokallikrein. Formed from the proenzyme, factor XII, by plasma kallikrein or factor XIIa. In peptidase family S1 (trypsin family)
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, CAS registry number: 75216-42-1
References:
1.  Fujikawa, K. and Davie, E.W. Human factor XII (Hageman factor). Methods Enzymol. 80 (1981) 198–211. [PMID: 6918768]
2.  Cho, K., Tanaka, T., Cook, R.R., Kisiel, W., Fujikawa, K., Kurachi, K. and Powers, J.C. Active-site mapping of bovine and human blood coagulation serine proteases using synthetic peptide 4-nitroanilide and thio ester substrates. Biochemistry 23 (1984) 644–650. [PMID: 6370301]
3.  Que, B.G. and Davie, E.W. Characterization of a cDNA coding for human factor XII (Hageman factor). Biochemistry 25 (1986) 1525–1528. [PMID: 3011063]
4.  Fujikawa, K. Bovine Hageman factor and its fragments. Methods Enzymol. 163 (1988) 54–68. [PMID: 3237089]
5.  Silverberg, M. and Kaplan, A.P. Human Hageman factor and its fragments. Methods Enzymol. 163 (1988) 68–80. [PMID: 3237092]
[EC 3.4.21.38 created 1981]
 
 
EC 3.4.21.39     
Accepted name: chymase
Reaction: Preferential cleavage: Phe┼ > Tyr┼ > Trp┼ > Leu┼
Other name(s): mast cell protease I; skeletal muscle protease; skin chymotryptic proteinase; mast cell serine proteinase, chymase; skeletal muscle (SK) protease
Comments: In mast cell granules. In peptidase family S1 (trypsin family)
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 97501-92-3
References:
1.  Woodbury, R.G., Everitt, M. and Neurath, H. Mast cell proteases. Methods Enzymol. 80 (1981) 588–609. [PMID: 7043202]
2.  Powers, J.C., Tanaka, T., Harper, J.W., Minematsu, Y., Barker, L., Lincoln, D., Crumley, K.V., Fraki, J.E., Schechter, N.M., Lazarus, G.G., Nakajima, K., Nakashino, K., Neurath, H. and Woodbury, R.G. Mammalian chymotrypsin-like enzymes. Comparative reactivities of rat mast cell proteases, human and dog skin chymases, and human cathepsin G with peptide 4-nitroanilide substrates and with peptide chloromethyl ketone and sulfonyl fluoride inhibitors. Biochemistry 24 (1985) 2048–2058. [PMID: 3893542]
3.  Johnson, L.A., Moon, K.E. and Eisenberg, M. Purification to homogeneity of the human skin chymotryptic proteinase "chymase". Anal. Biochem. 155 (1986) 358–364. [DOI] [PMID: 2425663]
[EC 3.4.21.39 created 1981]
 
 
EC 3.4.21.41     
Accepted name: complement subcomponent C1r
Reaction: Selective cleavage of Lys(or Arg)┼Ile bond in complement subcomponent C1s to form C1s (EC 3.4.21.42)
Other name(s): activated complement C1r; C1r esterase; activated complement C1r
Comments: Activated from proenzyme C1r in plasma during activation of the complement system by the "classical" route. In peptidase family S1 (trypsin family)
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 80295-69-8
References:
1.  Sim, R.B. The human complement system serine proteases C1r and C1s and their proenzymes. Methods Enzymol. 80 (1981) 26–42. [PMID: 6281620]
2.  Leytus, S.P., Kurachi, K., Sakariassen, K.S. and Davie, E.W. Nucleotide sequence of the cDNA coding for human complement C1r. Biochemistry 25 (1986) 4855–4863. [PMID: 3021205]
3.  Müller-Eberhard, H.J. Molecular organization and function of the complement system. Annu. Rev. Biochem. 57 (1988) 321–347. [DOI] [PMID: 3052276]
[EC 3.4.21.41 created 1981]
 
 
EC 3.4.21.42     
Accepted name: complement subcomponent C1s
Reaction: Cleavage of Arg┼Ala bond in complement component C4 to form C4a and C4b, and Lys(or Arg)┼Lys bond in complement component C2 to form C2a and C2b: the "classical" pathway C3 convertase
Other name(s): C1 esterase; activated complement C1s; complement C1r
Comments: Activated from proenzyme C1s in plasma by complement subcomponent C1r. In peptidase family S1 (trypsin family)
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 80295-70-1
References:
1.  Sim, R.B. The human complement system serine proteases C1r and C1s and their proenzymes. Methods Enzymol. 80 (1981) 26–42. [PMID: 6281620]
2.  MacKinnon, C.M., Carter, P.E., Smyth, S.J., Dunbar, B. and Fothergill, J.E. Molecular cloning of cDNA for human complement component C1s. The complete amino acid sequence. Eur. J. Biochem. 169 (1987) 547–553. [DOI] [PMID: 3500856]
3.  Müller-Eberhard, H.J. Molecular organization and function of the complement system. Annu. Rev. Biochem. 57 (1988) 321–347. [DOI] [PMID: 3052276]
4.  Skoog, M.T., Mehdi, S., Wiseman, J.S. and Bey, P. The specificity of two proteinases that cleave adjacent to arginine, C 1 esterase and acrosin, for peptide p-nitroanilide substrates. Biochim. Biophys. Acta 996 (1989) 89–94. [DOI] [PMID: 2500154]
[EC 3.4.21.42 created 1981]
 
 
EC 3.4.21.48     
Accepted name: cerevisin
Reaction: Hydrolysis of proteins with broad specificity, and of Bz-Arg-OEt Ac-Tyr-OEt. Does not hydrolyse peptide amides
Other name(s): yeast proteinase B; proteinase yscB; baker’s yeast proteinase B; brewer’s yeast proteinase; peptidase β
Comments: From Saccharomyces cerevisiae (baker’s yeast, brewer’s yeast). In peptidase family S8 (subtilisin family), but contains a Cys residue near the active site His, and is inhibited by mercurials. Proteinase ycaB is a similar enzyme from the yeast Candida albicans [3]
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, CAS registry number: 37288-81-6
References:
1.  Félix, F. and Brouillet, N. Purification et proprietes de deux peptidases de levure de brasserie. Biochim. Biophys. Acta 122 (1966) 127–144. [PMID: 4961236]
2.  Kominami, E., Hoffschulte, H., Leuschel, L., Maier, K. and Holzer, H. The substrate specificity of proteinase B from baker’s yeast. Biochim. Biophys. Acta 661 (1981) 136–141. [DOI] [PMID: 7028121]
3.  Farley, P.C., Shepherd, M.G. and Sullivan, P.A. The purification and properties of yeast proteinase B from Candida albicans. Biochem. J. 236 (1986) 177–184. [PMID: 3539100]
4.  Moehle, C.M., Tizard, R., Lemmon, S.K., Smart, J. and Jones, E.W. Protease B of the lysosome like vacuole of the yeast Saccharomyces cerevisiae is homologous to the subtilisin family of serine proteases. Mol. Cell. Biol. 7 (1987) 4390–4399. [DOI] [PMID: 3325823]
[EC 3.4.21.48 created 1972 as EC 3.4.22.9, transferred 1981 to EC 3.4.21.48]
 
 
EC 3.4.21.50     
Accepted name: lysyl endopeptidase
Reaction: Preferential cleavage: Lys┼, including -Lys┼Pro-
Other name(s): Achromobacter proteinase I (also see Comment); Achromobacter lyticus alkaline proteinase I; protease I; achromopeptidase; lysyl bond specific proteinase
Comments: From Achromobacter lyticus [6]. Enzymes with similar specificity are produced by Lysobacter enzymogenes (Endoproteinase Lys-C; [3]) and Pseudomonas aeruginosa (Ps-1; [4]). In peptidase family S1 (trypsin family)
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 123175-82-6
References:
1.  Masaki, T., Tanabe, M., Nakamura, K. and Soejima, M. Studies on a new proteolytic enzyme from Achromobacter lyticus M497-1. I. Purification and some enzymatic properties. Biochim. Biophys. Acta. 660 (1981) 44–50. [DOI] [PMID: 6791693]
2.  Masaki, T., Fujihasi, T., Nakamura, K. and Soejima, M. Studies on a new proteolytic enzyme from Achromobacter lyticus M497-1. II. Specificity and inhibition studies of Achromobacter protease I. Biochim. Biophys. Acta 660 (1981) 51–55. [DOI] [PMID: 6168293]
3.  Jekel, P.A., Weijer, W.J. and Beintema, J.J. Use of endoproteinase Lys-C from Lysobacter enzymogenes in protein sequence analysis. Anal. Biochem. 134 (1983) 347–354. [DOI] [PMID: 6359954]
4.  Elliott, B.W. and Cohen, C. Isolation and characterization of a lysine-specific protease from Pseudomonas aeruginosa. J. Biol. Chem. 261 (1986) 11259–11265. [PMID: 3090046]
5.  Ohara, T., Makino, K., Shinagawa, H., Nakata, A., Norioka, S. and Sakiyama, F. Cloning, nucleotide sequence, and expression of Achromobacter protease I gene. J. Biol. Chem. 264 (1989) 20625. [PMID: 2684982]
6.  Tsunasawa, S., Masaki, T., Hirose, M., Soejima, M. and Sakiyama, F. The primary structure and structural characteristics of Achromobacter lyticus protease I, a lysine-specific serine protease. J. Biol. Chem. 264 (1989) 3832–3839. [PMID: 2492988]
[EC 3.4.21.50 created 1983]
 
 
EC 3.4.21.53     
Accepted name: endopeptidase La
Reaction: Hydrolysis of proteins in presence of ATP
Other name(s): ATP-dependent serine proteinase; lon proteinase; protease La; proteinase La; ATP-dependent lon proteinase; ATP-dependent protease La; Escherichia coli proteinase La; Escherichia coli serine proteinase La; gene lon protease; gene lon proteins; PIM1 protease; PIM1 proteinase; serine protease La
Comments: Product of the lon gene in Escherichia coli. ATP hydrolysis is linked with peptide bond hydrolysis; vanadate inhibits both reactions. Type example of peptidase family S16. A similar enzyme occurs in animal mitochondria
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 79818-35-2
References:
1.  Desautels, M. and Goldberg, A.L. Demonstration of an ATP-dependent, vanadate-sensitive endoprotease in the matrix of rat liver mitochondria. J. Biol. Chem. 257 (1982) 11673–11679. [PMID: 6749845]
2.  Larimore, F.S., Waxman, L. and Goldberg, A.L. Studies of the ATP-dependent proteolytic enzyme, protease La, from Escherichia coli. J. Biol. Chem. 257 (1982) 4187–4195. [PMID: 7040380]
3.  Chin, D.T., Goff, S.A., Webster, T., Smith, T. and Goldberg, A.L. Sequence of the lon gene in Escherichia coli. A heat-shock gene which encodes the ATP-dependent protease La. J. Biol. Chem. 263 (1988) 11718–11728. [PMID: 3042779]
[EC 3.4.21.53 created 1986]
 
 
EC 3.4.21.59     
Accepted name: tryptase
Reaction: Preferential cleavage: Arg┼, Lys┼, but with more restricted specificity than trypsin
Other name(s): mast cell tryptase; mast cell protease II; skin tryptase; lung tryptase; pituitary tryptase; mast cell neutral proteinase; mast cell tryptase; mast cell neutral proteinase; mast cell serine proteinase II; mast cell proteinase II; mast cell serine proteinase tryptase; rat mast cell protease II; tryptase M
Comments: Occurs as a tetrameric molecule with high affinity for heparin, in mast cell granules. In peptidase family S1 (trypsin family). Not inhibited by α1-proteinase inhibitor or α2-macroglobulin
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 97501-93-4
References:
1.  Tanaka, T., McRae, B.J., Cho, K., Cook, R., Fraki, J.E., Johnson, D.A. and Powers, J.C. Mammalian tissue trypsin-like enzymes. Comparative reactivities of human skin tryptase, human lung tryptase, and bovine trypsin with peptide 4-nitroanilide and thioester substrates. J. Biol. Chem. 258 (1983) 13552–13557. [PMID: 6358206]
2.  Kido, H., Fukusen, N. and Katunuma, N. Chymotrypsin- and trypsin-type serine proteases in rat mast cells: properties and functions. Arch. Biochem. Biophys 239 (1985) 436–443. [DOI] [PMID: 3890754]
3.  Cromlish, J.A., Seidah, N.G., Marcinkiewitz, M., Hamelin, J., Johnson, D.A. and Chrétien, M. Human pituitary tryptase: molecular forms, NH2-terminal sequence, immunocytochemical localization, and specificity with prohormone and fluorogenic substrates. J. Biol. Chem. 262 (1987) 1363–1373. [PMID: 3543004]
4.  Harvima, I.T., Schechter, N.M., Harvima, R.J. and Fräki, J.E. Human skin tryptase: purification, partial characterization and comparison with human lung tryptase. Biochim. Biophys. Acta 957 (1988) 71–80. [DOI] [PMID: 3140898]
5.  Vanderslice, P., Ballinger, S.M., Tam, E.K., Goldstein, S.M., Craik, C.S. and Caughey, G. Human mast cell tryptase: multiple cDNAs and genes reveal a multigene serine protease family. Proc. Natl. Acad. Sci. USA 87 (1990) 3811–3815. [DOI] [PMID: 2187193]
[EC 3.4.21.59 created 1992]
 
 
EC 3.4.21.61     
Accepted name: kexin
Reaction: Cleavage of -Lys-Arg┼ and -Arg-Arg┼ bonds to process yeast α-factor pheromone and killer toxin precursors
Other name(s): yeast KEX2 protease; proteinase yscF; prohormone-processing endoprotease; paired-basic endopeptidase; yeast cysteine proteinase F (misleading); paired-basic endopeptidase; andrenorphin-Gly-generating enzyme; endoproteinase Kex2p; gene KEX2 dibasic proteinase; Kex 2p proteinase; Kex2 endopeptidase; Kex2 endoprotease; Kex2 endoproteinase; Kex2 protease; proteinase Kex2p; Kex2-like precursor protein processing endoprotease; prohormone-processing KEX2 proteinase; prohormone-processing proteinase; proprotein convertase; protease KEX2; Kex2 proteinase; Kex2-like endoproteinase
Comments: A Ca2+-activated peptidase of peptidase family S8, containing Cys near the active site His, and inhibited by p-mercuribenzoate. Similar enzymes occur in mammals.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 99676-46-7
References:
1.  Julius, D., Brake, A., Blair, L., Kunisawa, R. and Thorner, J. Isolation of the putative structural gene for the lysine-arginine-cleaving endopeptidase required for processing of yeast prepro-α-factor. Cell 37 (1984) 1075–1089. [DOI] [PMID: 6430565]
2.  Achstetter, T. and Wolf, D.H. Hormone processing and membrane-bound proteinases in yeast. EMBO J. 4 (1985) 173–177. [PMID: 3894003]
3.  Mizuno, K., Nakamura, T., Ohshima, T., Tanaka, S. and Matsuo, H. Yeast KEX2 gene encodes an endopeptidase homologous to subtilisin-like serine proteases. Biochem. Biophys. Res. Commun. 156 (1988) 246–254. [DOI] [PMID: 2845974]
4.  Fuller, R.S., Brake, A. and Thorner, J. Yeast prohormone processing enzyme (KEX2 gene product) is a Ca2+-dependent serine protease. Proc. Natl. Acad. Sci. USA 86 (1989) 1434–1438. [DOI] [PMID: 2646633]
5.  Mizuno, K., Nakamura, T., Ohshima, T., Tanaka, S. and Matsuo, H. Characterization of KEX2-encoded endopeptidase from yeast Saccharomyces cerevisiae. Biochem. Biophys. Res. Commun. 159 (1989) 305–311. [DOI] [PMID: 2647083]
[EC 3.4.21.61 created 1989 as EC 3.4.22.23, transferred 1992 to EC 3.4.21.61]
 
 
EC 3.4.21.62     
Accepted name: subtilisin
Reaction: Hydrolysis of proteins with broad specificity for peptide bonds, and a preference for a large uncharged residue in P1. Hydrolyses peptide amides
Other name(s): alcalase; alcalase 0.6L; alcalase 2.5L; ALK-enzyme; bacillopeptidase A; bacillopeptidase B; Bacillus subtilis alkaline proteinase bioprase; bioprase AL 15; bioprase APL 30; colistinase; (see also comments); subtilisin J; subtilisin S41; subtilisin Sendai; subtilisin GX; subtilisin E; subtilisin BL; genenase I; esperase; maxatase; alcalase; thermoase PC 10; protease XXVII; thermoase; superase; subtilisin DY; subtilopeptidase; SP 266; savinase 8.0L; savinase 4.0T; kazusase; protease VIII; opticlean; Bacillus subtilis alkaline proteinase; protin A 3L; savinase; savinase 16.0L; savinase 32.0 L EX; orientase 10B; protease S
Comments: Subtilisin is a serine endopeptidase, type example of peptidase family S8. It contains no cysteine residues (although these are found in homologous enzymes). Species variants include subtilisin BPN′ (also subtilisin B, subtilopeptidase B, subtilopeptidase C, Nagarse, Nagarse proteinase, subtilisin Novo, bacterial proteinase Novo) and subtilisin Carlsberg (subtilisin A, subtilopeptidase A, alcalase Novo). Similar enzymes are produced by various Bacillus subtilis strains and other Bacillus species [1,3]
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 9014-01-1
References:
1.  Ottesen, M. and Svendsen, I. The subtilisins. Methods Enzymol. 19 (1970) 199–215.
2.  Markland, F.S. and Smith, E.L. Subtilisins: primary structure, chemical and physical properties. In: Boyer, P.D. (Ed.), The Enzymes, 3rd edn, vol. 3, Academic Press, New York, 1971, pp. 561–608.
3.  Philipp, M. and Bender, M.L. Kinetics of subtilisin and thiolsubtilisin. Mol. Cell. Biochem. 51 (1983) 5–32. [PMID: 6221910]
4.  Nedkov, P., Oberthür, W. and Braunitzer, G. Determination of the complete amino acid sequence of subtilisin DY and its comparison with the primary structures of the subtilisins BPN, Carlsberg and amylosacchariticus. Biol. Chem. Hoppe-Seyler 366 (1985) 421–430. [PMID: 3927935]
5.  Ikemura, H., Takagi, H. and Inouye, M. Requirement of pro-sequence for the production of active subtilisin E in Escherichia coli. J. Biol. Chem. 262 (1987) 7859–7864. [PMID: 3108260]
6.  Polgár, L. Structure and function of serine proteases. In: Neuberger, A. and Brocklehurst, K. (Eds), New Comprehensive Biochemistry: Hydrolytic Enzymes, vol. 16, Elsevier, Amsterdam, 1987, pp. 159–200.
[EC 3.4.21.62 created 1992 (EC 3.4.21.14 created 1961 as EC 3.4.4.16, transferred 1972 to EC 3.4.21.14, modified 1986, part incorporated 1992)]
 
 
EC 3.4.21.63     
Accepted name: oryzin
Reaction: Hydrolysis of proteins with broad specificity, and of Bz-Arg-OEt > Ac-Tyr-OEt. Does not hydrolyse peptide amides
Other name(s): Aspergillus alkaline proteinase; aspergillopeptidase B; API 21; aspergillopepsin B; aspergillopepsin F; Aspergillus candidus alkaline proteinase; Aspergillus flavus alkaline proteinase; Aspergillus melleus semi-alkaline proteinase; Aspergillus oryzae alkaline proteinase; Aspergillus parasiticus alkaline proteinase; Aspergillus serine proteinase; Aspergillus sydowi alkaline proteinase; Aspergillus soya alkaline proteinase; Aspergillus melleus alkaline proteinase; Aspergillus sulphureus alkaline proteinase; prozyme; P 5380; kyorinase; seaprose S; semi-alkaline protease; sumizyme MP; prozyme 10; onoprose; onoprose SA; protease P; promelase
Comments: A peptidase of family S8 (subtilisin family), not containing cysteine, that is the predominant extracellular alkaline endopeptidase of the mold Aspergillus oryzae. Identical or closely related enzymes are produced by A. flavus and A. sojae [2,3,4]
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, CAS registry number: 9074-07-1
References:
1.  Nakagawa, Y. Alkaline proteinases from Aspergillus. Methods Enzymol. 19 (1970) 581–591.
2.  Hayashi, K. and Terada, M. Some characteristics of hydrolysis of synthetic substrates and proteins by the alkaline proteases from Aspergillus sojae. Agric. Biol. Chem. 36 (1972) 1755–1765.
3.  Turková, J., Mikes, O., Hayashi, K., Danno, G. and Polgár, L. Alkaline proteinases of the genus Aspergillus. Biochim. Biophys. Acta 257 (1972) 257–263. [DOI] [PMID: 4623338]
4.  Morihara, K., Oka, T. and Tsuzuki, H. Comparative study of various serine alkaline proteinases from microorganisms. Esterase activity against N-acylated peptide ester substrates. Arch. Biochem. Biophys. 165 (1974) 72–79. [DOI] [PMID: 4441086]
5.  Spadari, S., Subramanian, A.R. and Kalnitsky, G. Highly restricted specificity of the serine proteinase aspergillopeptidase B. Biochim. Biophys. Acta 359 (1974) 267–272. [DOI] [PMID: 4859351]
[EC 3.4.21.63 created 1992 (EC 3.4.21.14 created 1961 as EC 3.4.4.16, transferred 1972 to EC 3.4.21.14, modified 1986, part incorporated 1992)]
 
 
EC 3.4.21.66     
Accepted name: thermitase
Reaction: Hydrolysis of proteins, including collagen
Other name(s): thermophilic Streptomyces serine proteinase; Thermoactinomyces vulgaris serine proteinase
Comments: A peptidase of family S8 (subtilisin family) from Thermoactinomyces vulgaris containing a single Cys, near the active site His, and inhibited by p-mercuribenzoate. The N-terminal extension of the polypeptide chain relative to subtilisin contributes to Ca2+-binding and the high thermostability. The amino acid composition and properties of the thermostable enzyme from Streptomyces rectus var. proteolyticus (formerly included in EC 3.4.21.14) are closely similar [1,2].
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 69772-87-8
References:
1.  Mizusawa, K. and Yoshida, F. Thermophilic Streptomyces alkaline proteinase. J. Biol. Chem. 247 (1972) 6978–6984. [PMID: 4711613]
2.  Borgia, P. and Campbell, L. Properties of two homologous alkaline proteases from Streptomyces rectus. J. Bacteriol. 123 (1974) 1109–1115. [PMID: 4373436]
3.  Kleine, R. Properties of thermitase, a thermostable serine protease from Thermoactinomyces vulgaris. Acta Biol. Med. Ger. 41 (1982) 89–102. [PMID: 7051706]
4.  Meloun, B., Baudyš, M., Kostka, V., Hausdorf, G., Frömmel, C. and Höhne, W.E. Complete primary structure of thermitase from Thermoactinomyces vulgaris and its structural features related to the subtilisin-type proteinases. FEBS Lett. 183 (1985) 195–200.
5.  Teplyakov, A.V., Kuranova, I.P., Harutyunyan, E.H., Vainshtein, B.K., Frömmel, C., Höhne, W.E. and Wilson, K.S. Crystal structure of thermitase at 1.4 Å resolution. J. Mol. Biol. 214 (1990) 261–279. [DOI] [PMID: 2196375]
[EC 3.4.21.66 created 1992]
 
 
EC 3.4.21.67     
Accepted name: endopeptidase So
Reaction: Hydrolysis of proteins, but not Bz-Tyr-OEt, Ac-Phe-β-naphthylester, or Bz-Arg-OEt
Other name(s): E. coli cytoplasmic proteinase; proteinase So; Escherichia coli serine proteinase So
Comments: An Escherichia coli cytoplasmic endopeptidase formerly included in EC 3.4.21.14. Inhibited by Tos-Phe-CH2Cl, but not by Tos-Lys-CH2Cl
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, CAS registry number: 81611-83-8
References:
1.  Goldberg, A.L., Swamy, K.H.S., Chung, C.H. and Larimore, F.S. Proteases in Escherichia coli. Methods Enzymol. 80 (1981) 680–702. [PMID: 7043205]
2.  Chung, C.H. and Goldberg, A.L. Purification and characterization of protease So, a cytoplasmic serine protease in Escherichia coli. J. Bacteriol. 154 (1983) 231–238. [PMID: 6339474]
[EC 3.4.21.67 created 1992 (EC 3.4.21.14 created 1961 as EC 3.4.4.16, transferred 1972 to EC 3.4.21.14, modified 1986, part incorporated 1992)]
 
 
EC 3.4.21.70     
Accepted name: pancreatic endopeptidase E
Reaction: Preferential cleavage: Ala┼. Does not hydrolyse elastin
Other name(s): cholesterol-binding proteinase; proteinase E; cholesterol-binding serine proteinase; pancreatic protease E; pancreatic proteinase E; cholesterol-binding pancreatic proteinase; CBPP; pancreas E proteinase
Comments: A peptidase of family S1 (trypsin family) from pancreatic juice. Unlike elastases, has an acidic pI. Binds cholesterol
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, CAS registry number: 68073-27-8
References:
1.  Mallory, P.A. and Travis, J. Human pancreatic enzymes: purification and characterization of a nonelastolytic enzyme, protease E, resembling elastase. Biochemistry 14 (1975) 722–729. [PMID: 234742]
2.  Shen, W., Fletcher, T.S. and Largman, C. Primary structure of human pancreatic protease E determined by sequence analysis of the cloned mRNA. Biochemistry 26 (1987) 3447–3452. [PMID: 3477287]
[EC 3.4.21.70 created 1992]
 
 
EC 3.4.21.72     
Accepted name: IgA-specific serine endopeptidase
Reaction: Cleavage of immunoglobulin A molecules at certain Pro┼ bonds in the hinge region. No small molecule substrates are known
Other name(s): IgA protease; IgA proteinase; IgA-specific proteinase; immunoglobulin A protease; immunoglobulin A proteinase
Comments: Species variants differing slightly in specificity are secreted by Gram-negative bacteria Neisseria gonorrhoeae and Haemophilus influenzae. Type example of peptidase family S6. Some other bacterial endopeptidases with similar specificity are of metallo- type (see EC 3.4.24.13, IgA-specific metalloendopeptidase)
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, CAS registry number: 55127-02-1
References:
1.  Plaut, A.G. The IgA1 proteases of pathogenic bacteria. Annu. Rev. Microbiol. 37 (1983) 603–622. [DOI] [PMID: 6416146]
2.  Bachovchin, W.W., Plaut, A.G., Flentke, G.R., Lynch, M. and Kettner, C.A. Inhibition of IgA1 proteinases from Neisseria gonorrhoeae and Hemophilus influenzae by peptide prolyl boronic acids. J. Biol. Chem. 265 (1990) 3738–3743. [PMID: 2105953]
[EC 3.4.21.72 created 1992]
 
 
EC 3.4.21.73     
Accepted name: u-plasminogen activator
Reaction: Specific cleavage of Arg┼Val bond in plasminogen to form plasmin
Other name(s): urokinase; urinary plasminogen activator; cellular plasminogen activator; urokinase-type plasminogen activator; double-chain urokinase-type plasminogen activator; two-chain urokinase-type plasminogen activator; urokinase plasminogen activator; uPA; u-PA; abbokinase; urinary esterase A
Comments: Formed from the inactive precursor by action of plasmin or plasma kallikrein. Differs in structure from t-plasminogen activator (EC 3.4.21.68), and does not bind to fibrin. In peptidase family S1 (trypsin family). Formerly included in EC 3.4.21.31 and EC 3.4.99.26
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 9039-53-6
References:
1.  Lottenberg, R., Christiansen, U., Jackson, C.M. and Coleman, P.L. Assay of coagulation proteases using peptide chromogenic and fluorogenic substrates. Methods Enzymol. 80 (1981) 341–361. [PMID: 6210826]
2.  Loskutoff, D.J. and Schleef, R.R. Plasminogen activators and their inhibitors. Methods Enzymol. 163 (1988) 293–302. [PMID: 3148826]
3.  Saksela, O. and Rifkin, D.B. Cell-associated plasminogen activation: regulation and physiological functions. Annu. Rev. Cell Biol. 4 (1988) 93–126. [DOI] [PMID: 3143380]
4.  Collen, D., Lijnen, H. R. and Verstraete, M. The fibrinolytic system and its disorders. In: Handin, R.I., Lux, S.E. and Stossel, J.P. (Eds), Blood: Principles and Practice of Hematology, 2nd edn, J.B.Lippincott Company, Philadelphia, 1990.
5.  Lijnen, H.R., Van Hoef, B., Nelles, L. and Collen, D. Plasminogen activation with single-chain urokinase-type plasminogen activator (scu-PA). Studies with active site mutagenized plasminogen (Ser740→Glu). J. Biol. Chem. 265 (1990) 5232–5236. [PMID: 1969415]
[EC 3.4.21.73 created 1972 as EC 3.4.99.26, transferred 1978 as EC 3.4.21.31, part transferred 1992 to EC 3.4.21.73]
 
 
EC 3.4.21.75     
Accepted name: furin
Reaction: Release of mature proteins from their proproteins by cleavage of -Arg-Xaa-Yaa-Arg┼ bonds, where Xaa can by any amino acid and Yaa is Arg or Lys. Releases albumin, complement component C3 and von Willebrand factor from their respective precursors
Other name(s): prohormone convertase; dibasic processing enzyme; PACE; paired basic amino acid cleaving enzyme; paired basic amino acid converting enzyme; serine proteinase PACE; PC1; SPC3; proprotein convertase
Comments: One of a group of peptidases in peptidase family S8 (subtilisin family) that is structurally and functionally similar to kexin. All are activated by Ca2+, contain Cys near the active site His, and are inhibited by p-mercuribenzoate. At least three related enzymes are recognized in mammals: PC2, PC3 and PC4, which have somewhat different specificities
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 141760-45-4
References:
1.  Van de Ven, W.J.M., Voorberg, J., Fontijn, R., Pannekoek, H., van den Ouweland, A.M.W., van Duijnhoven, H.L.P., Roebroek, A.J.M. and Siezen, R.J. Furin is a subtilisin-like proprotein processing enzyme in higher eukaryotes. Mol. Biol. Rep. 14 (1990) 265–275. [PMID: 2094803]
2.  Van de Ven, W.J.M., Creemers, J.W.M. and Roebroek, A.J.M. Furin: the prototype mammalian subtilisin-like proprotein-processing enzyme. Endoproteolytic cleavage at paired basic residues of proproteins of the eukaryotic secretory pathway. Enzyme 45 (1991) 257–270. [PMID: 1843280]
3.  Hatsuzawa, K., Murakami, K. and Nakayama, K. Molecular and enzymatic properties of furin, a Kex2-like endoprotease involved in precursor cleavage at Arg-X-Lys/Arg-Arg sites. J. Biochem. (Tokyo) 111 (1992) 296–301. [PMID: 1587790]
4.  Seidah, N.G. and Chrétien, M. Proprotein and prohormone convertases of the subtilisin family: recent developments and future perspectives. Trends Endocrinol. Metab. 3 (1992) 133–140. [PMID: 18407092]
5.  Steiner, D.F., Smeekens, S.P., Ohagi, S. and Chan, S.J. The new enzymology of precursor processing endoproteases. J. Biol. Chem. 267 (1992) 23435–23438. [PMID: 1429684]
[EC 3.4.21.75 created 1993]
 
 
EC 3.4.21.78     
Accepted name: granzyme A
Reaction: Hydrolysis of proteins, including fibronectin, type IV collagen and nucleolin. Preferential cleavage: -Arg┼, -Lys┼ >> -Phe┼ in small molecule substrates
Other name(s): CTLA3; HuTPS; T-cell associated protease 1; cytotoxic T lymphocyte serine protease; TSP-1; T-cell derived serine proteinase
Comments: From cytotoxic T lymphocyte granules. In peptidase family S1 (trypsin family). The human enzyme does not cleave Phe┼-
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 143180-73-8
References:
1.  Simon, M.M., Hoschützky, H., Fruth, U., Simon, H.-G. and Kramer, M.D. Purification and characterization of a T cell specific serine proteinase (TSP-1) from cloned cytolytic T lymphocytes. EMBO J. 5 (1986) 3267–3274. [PMID: 3545816]
2.  Gershenfeld, H.K., Hershberger, R.J., Shows, T.B. and Weissman, I.L. Cloning and chromosomal assignment of a human cDNA encoding a T cell- and natural killer cell-specific trypsin-like serine protease. Proc. Natl. Acad. Sci. USA 85 (1988) 1184–1188. [DOI] [PMID: 3257574]
3.  Odake, S., Kam, C.-M., Narasimhan, L., Poe, M., Blake, J.T., Krahenbuhl, O., Tschopp, J. and Powers, J.C. Human and murine cytotoxic T lymphocyte serine proteases: subsite mapping with peptide thioester substrates and inhibition of enzyme activity and cytolysis by isocoumarins. Biochemistry 30 (1991) 2217–2227. [PMID: 1998680]
[EC 3.4.21.78 created 1993]
 
 
EC 3.4.21.79     
Accepted name: granzyme B
Reaction: Preferential cleavage: -Asp┼ >> -Asn┼ > -Met┼, -Ser┼
Other name(s): CTLA1; CCPII; cytotoxic cell proteinase-1; granzyme G; granzyme H; CCP1 proteinase
Comments: From cytotoxic T lymphocyte granules. In peptidase family S1 (trypsin family)
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 143180-74-9
References:
1.  Schmid, J. and Weissmann, C. Induction of mRNA for a serine protease and a β-thromboglobulin-like protein in mitogen-stimulated human leukocytes. J. Immunol. 139 (1987) 250–256. [PMID: 2953813]
2.  Odake, S., Kam, C.-M., Narasimhan, L., Poe, M., Blake, J.T., Krahenbuhl, O., Tschopp, J. and Powers, J.C. Human and murine cytotoxic T lymphocyte serine proteases: subsite mapping with peptide thioester substrates and inhibition of enzyme activity and cytolysis by isocoumarins. Biochemistry 30 (1991) 2217–2227. [PMID: 1998680]
3.  Poe, M., Blake, J.T., Boulton, D.A., Gammon, M., Sigal, N.H., Wu, J.K. and Zweerink, H.J. Human cytotoxic lymphocyte granzyme B. Its purification from granules and the characterization of substrate and inhibitor specificity. J. Biol. Chem. 266 (1991) 98–103. [PMID: 1985927]
[EC 3.4.21.79 created 1993]
 
 
EC 3.4.21.80     
Accepted name: streptogrisin A
Reaction: Hydrolysis of proteins with specificity similar to chymotrypsin
Other name(s): Streptomyces griseus protease A; protease A; proteinase A; Streptomyces griseus proteinase A; Streptomyces griseus serine proteinase 3; Streptomyces griseus serine proteinase A
Comments: From Streptomyces griseus. A component of Pronase, in family S1 (trypsin family). Not inhibited by Tos-Phe-CH2Cl or ovomucoid
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, CAS registry number: 55326-50-6
References:
1.  Johnson, P. and Smillie, L.B. The disulfide bridge sequences of a serine protease of wide specificity from Streptomyces griseus. Can. J. Biochem. 49 (1971) 548–562. [PMID: 5575653]
2.  Sielecki, A.R., Hendrickson, W.A., Broughton, C.G., Delbaere, L.T.J., Brayer, G.D. and James, M.N.G. Protein structure refinement: Streptomyces griseus serine protease A at 1.8 Å resolution. J. Mol. Biol. 134 (1979) 781–804. [DOI] [PMID: 119870]
3.  James, M.N.G., Sielecki, A.R., Brayer, G.D., Delbaere, L.T.J. and Bauer, C.-A. Structures of product and inhibitor complexes of Streptomyces griseus protease A at 1.8 Å resolution. J. Mol. Biol. 144 (1980) 43–88. [DOI] [PMID: 6783761]
4.  Delbaere, L.T.J. and Brayer, G.D. The 1.8 Å structure of the complex between chymostatin and Streptomyces griseus protease A. A model for serine protease catalytic tetrahedral intermediates. J. Mol. Biol. 183 (1985) 89–103. [DOI] [PMID: 3892018]
5.  Henderson, G., Krygsman, P., Liu, C.J., Davey, C.C. and Malek, L.T. Characterization and structure of genes for proteases A and B from Streptomyces griseus. J. Bacteriol. 169 (1987) 3778–3784. [DOI] [PMID: 3112129]
[EC 3.4.21.80 created 1993]
 
 
EC 3.4.21.81     
Accepted name: streptogrisin B
Reaction: Hydrolysis of proteins with trypsin-like specificity
Other name(s): Streptomyces griseus protease B; pronase B; serine proteinase B; Streptomyces griseus proteinase B; Streptomyces griseus proteinase 1; Streptomyces griseus serine proteinase B
Comments: From Streptomyces griseus. A component of Pronase, in peptidase family S1 (trypsin family), distinct from Streptomyces trypsin
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 55071-87-9
References:
1.  Jurasek, L., Fackre, D. and Smillie, L.B. Remarkable homology about the disulfide bridges of a trypsin-like enzyme from Streptomyces griseus. Biochem. Biophys. Res. Commun. 37 (1969) 99–105. [DOI] [PMID: 4899581]
2.  Fujinaga, M., Read, R.J., Sielecki, A., Ardelt, W., Laskowski, M., Jr. and James, M.N.G. Refined crystal structure of the molecular complex of Streptomyces griseus protease B, a serine protease, with the third domain of the ovomucoid inhibitor from turkey. Proc. Natl Acad. Sci. USA 79 (1982) 4868–4872. [DOI] [PMID: 6750612]
3.  Read, R.J., Fujinaga, M., Sielecki, A.R. and James, M.N.G. Structure of the complex of Streptomyces griseus protease B and the third domain of turkey ovomucoid inhibitor at 1.8-Å resolution. Biochemistry 22 (1983) 4420–4433. [PMID: 6414511]
4.  Henderson, G., Krygsman, P., Liu, C.J., Davey, C.C. and Malek, L.T. Characterization and structure of genes for proteases A and B from Streptomyces griseus. J. Bacteriol. 169 (1987) 3778–3784. [DOI] [PMID: 3112129]
5.  Greenblatt, H.M., Ryan, C.A. and James, M.N.G. Structure of the complex of Streptomyces griseus proteinase B and polypeptide chymotrypsin inhibitor-1 from Russet Burbank potato tubers at 2.1 Å resolution. J. Mol. Biol. 205 (1989) 201–228. [DOI] [PMID: 2494344]
[EC 3.4.21.81 created 1993]
 
 
EC 3.4.21.82     
Accepted name: glutamyl endopeptidase II
Reaction: Preferential cleavage: -Glu┼ >> -Asp┼ . Preference for Pro or Leu at P2 and Phe at P3. Cleavage of -Glu┼Asp- and -Glu┼Pro- bonds is slow
Other name(s): GluSGP
Comments: From Streptomyces griseus. A peptidase of family S1 (trypsin family). Inhibited by [Leu18→Glu]-modified turkey ovomucoid third domain
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 137010-42-5
References:
1.  Yoshida, N., Tsuruyama, S., Nagata, K., Hirayama, K., Noda, K. and Makisumi, S. Purification and characterization of an acidic amino acid specific endopeptidase of Streptomyces griseus obtained from a commercial preparation (Pronase). J. Biochem. (Tokyo) 104 (1988) 451–456. [PMID: 3149277]
2.  Komiyama, T., Bigler, T.L., Yoshida, N., Noda, K. and Laskowski, M., Jr. Replacement of P1 Leu18 by Glu18 in the reactive site of turkey ovomucoid third domain converts it into a strong inhibitor of Glu-specific Streptomyces griseus Proteinase (GluSGP). J. Biol. Chem. 266 (1991) 10727–10730. [PMID: 1674942]
3.  Nagata, K., Yoshida, N., Ogata, F., Araki, M. and Noda, K. Subsite mapping of an acidic amino acid-specific endopeptidase from Streptomyces griseus, GluSGP, and protease V8. J. Biochem. (Tokyo) 110 (1991) 859–862. [PMID: 1794975]
4.  Svendsen, I., Jensen, M.R. and Breddam, K. The primary structure of the glutamic acid-specific protease of Streptomyces griseus. FEBS Lett. 292 (1991) 165–167. [DOI] [PMID: 1959600]
5.  Breddam, K. and Meldal, M. Substrate preferences of glutamic-acid-specific endopeptidases assessed by synthetic peptide substrates based on intramolecular fluorescence quenching. Eur. J. Biochem. 206 (1992) 103–107. [DOI] [PMID: 1587264]
[EC 3.4.21.82 created 1993]
 
 
EC 3.4.21.83     
Accepted name: oligopeptidase B
Reaction: Hydrolysis of -Arg┼, -Lys┼ bonds in oligopeptides, even when P1′ residue is proline
Other name(s): protease II; Escherichia coli alkaline proteinase II; protease II
Comments: Known from Escherichia coli. Inhibited by Tos-Lys-CH2Cl. In peptidase family S9 (prolyl oligopeptidase family)
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, CAS registry number: 57657-67-7
References:
1.  Kanatani, A., Masuda, T., Shimoda, T., Misoka, F., Lin, X.S., Yoshimoto, T. and Tsuru, D. Protease II from Escherichia coli: sequencing and expression of the enzyme gene and characterization of the expressed enzyme. J. Biochem. (Tokyo) 110 (1991) 315–320. [PMID: 1769955]
[EC 3.4.21.83 created 1993]
 
 
EC 3.4.21.84     
Accepted name: limulus clotting factor C
Reaction: Selective cleavage of -Arg103┼Ser- and -Ile124┼Ile- bonds in limulus clotting factor B to form factor B. Cleavage of -Pro-Arg┼ bonds in synthetic substrates
Other name(s): factor C; limulus factor C
Comments: From the hemocyte granules of the horseshoe crabs Limulus and Tachypleus. Factor C is activated by Gram-negative bacterial lipopolysaccharides and chymotrypsin. Inhibited by antithrombin III. In peptidase family S1 (trypsin family)
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, CAS registry number: 115743-27-6
References:
1.  Nakamura, T., Morita, T. and Iwanaga, S. Lipopolysaccharide-sensitive serine-protease zymogen (factor C) found in Limulus hemocytes. Isolation and characterization. Eur. J. Biochem. 154 (1986) 511–521. [DOI] [PMID: 3512266]
2.  Muta, T., Miyata, T., Misumi, Y., Tokunaga, F., Nakamura, T., Toh, Y., Ikehara, Y. and Iwanaga, S. Limulus factor C. An endotoxin-sensitive serine protease zymogen with a mosaic structure of complement-like, epidermal growth factor-like, and lectin-like domains. J. Biol. Chem. 266 (1991) 6554–6561. [PMID: 2007602]
3.  Tokunaga, F., Nakajima, H. and Iwanaga, S. Further studies on lipopolysaccharide-sensitive serine protease zymogen (factor C): its isolation from Limulus polyphemus hemocytes and identification as an intracellular zymogen activated by α-chymotrypsin, not by trypsin. J. Biochem. (Tokyo) 109 (1991) 150–157. [PMID: 2016264]
[EC 3.4.21.84 created 1993]
 
 
EC 3.4.21.86     
Accepted name: limulus clotting enzyme
Reaction: Selective cleavage of -Arg18┼ and -Arg47┼ bonds in coagulogen to form coagulin and fragments
Other name(s): clotting enzyme
Comments: From the hemocyte granules of horseshoe crabs Limulus and Tachypleus. Proclotting enzyme is activated by limulus clotting factor . In peptidase family S1 (trypsin family)
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS
References:
1.  Muta, T., Hashimoto, R., Miyata, T., Nishimura, H., Toh, Y. and Iwanaga, S. Proclotting enzyme from horseshoe crab hemocytes. cDNA cloning, disulfide locations, and subcellular localization. J. Biol. Chem. 265 (1990) 22426–22433. [PMID: 2266134]
2.  Tokunaga, F., Nakajima, H. and Iwanaga, S. Further studies on lipopolysaccharide-sensitive serine protease zymogen (factor C): its isolation from Limulus polyphemus hemocytes and identification as an intracellular zymogen activated by α-chymotrypsin, not by trypsin. J. Biochem. (Tokyo) 109 (1991) 150–157. [PMID: 2016264]
[EC 3.4.21.86 created 1993]
 
 
EC 3.4.21.87      
Transferred entry: omptin. Now EC 3.4.23.49, omptin. The enzyme is not a serine protease, as thought previously, but an aspartate protease
[EC 3.4.21.87 created 1993, deleted 2006]
 
 
EC 3.4.21.89     
Accepted name: signal peptidase I
Reaction: Cleavage of hydrophobic, N-terminal signal or leader sequences
Other name(s): leader peptidase I; signal proteinase; Escherichia coli leader peptidase; eukaryotic signal peptidase; eukaryotic signal proteinase; leader peptidase; leader peptide hydrolase; leader proteinase; signal peptidase; pilin leader peptidase; SPC; prokaryotic signal peptidase; prokaryotic leader peptidase; HOSP; prokaryotic signal proteinase; propeptidase; PuIO prepilin peptidase; signal peptide hydrolase; signal peptide peptidase; signalase; bacterial leader peptidase 1; pilin leader peptidase
Comments: The enzyme is found in bacterial membranes and in chloroplast thylakoid membranes. Unaffected by inhibitors of most serine peptidases, but site-directed mutagenesis implicates a Ser/Lys catalytic dyad in activity [1,3]. Hydrolyses a single bond -Ala┼Ala- in M13 phage procoat protein, producing free signal peptide and coat protein. Formerly included in EC 3.4.99.36. Eukaryote signal peptidases that may have somewhat different specificity are known from the endoplasmic reticulum membrane [4] and mitochondrial inner membrane [2]. Type example of peptidase family S26
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 65979-36-4
References:
1.  Black, M.T. Evidence that the catalytic activity of prokaryote leader peptidase depends upon the operation of a serine-lysine catalytic dyad. J. Bacteriol. 175 (1993) 4957–4961. [DOI] [PMID: 8394311]
2.  Nunnari, J., Fox, T.D. and Walter, P. A mitochondrial protease with two catalytic subunits of nonoverlapping specificities. Science 262 (1993) 1997–2004. [DOI] [PMID: 8266095]
3.  Tschantz, W.R., Sung, M., Delgado-Partin, V.M. and Dalbey, R.E. A serine and a lysine residue implicated in the catalytic mechanism of the Escherichia coli leader peptidase. J. Biol. Chem. 268 (1993) 27349–27354. [PMID: 8262975]
4.  Lively, M.O., Newsome, A.L. and Nusier, M. Eukaryote microsomal signal peptidases. Methods Enzymol. 244 (1994) 301–314. [DOI] [PMID: 7845216]
5.  Tschantz, W.R. and Dalbey, R.E. Bacterial leader peptidase I. Methods Enzymol. 244 (1994) 285–301. [DOI] [PMID: 7845215]
6.  Chaal, B.K., Mould, R.M., Barbrook, A.C., Gray, J.C. and Howe, C.J. Characterization of a cDNA encoding the thylakoidal processing peptidase from Arabidopsis thaliana. Implications for the origin and catalytic mechanism of the enzyme. J. Biol. Chem. 273 (1998) 689–692. [DOI] [PMID: 9422718]
7.  Inoue, K., Baldwin, A.J., Shipman, R.L., Matsui, K., Theg, S.M. and Ohme-Takagi, M. Complete maturation of the plastid protein translocation channel requires a type I signal peptidase. J. Cell Biol. 171 (2005) 425–430. [DOI] [PMID: 16275749]
[EC 3.4.21.89 created 1984 as EC 3.4.99.36, transferred 1995 to EC 3.4.21.89]
 
 
EC 3.4.21.90     
Accepted name: togavirin
Reaction: Autocatalytic release of the core protein from the N-terminus of the togavirus structural polyprotein by hydrolysis of a -Trp┼Ser- bond
Other name(s): Sindbis virus protease; Sindbis virus core protein; NsP2 proteinase
Comments: Known from the Sindbis and Semliki forest togaviruses. Once released, the core protein does not retain catalytic activity. Togavirin is the type example of peptidase family S3 and has a similar tertiary structure to chymotrypsin [3]
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, CAS registry number: 342882-56-8
References:
1.  Kräusslich, H.-G. and Wimmer, E. Viral proteinases. Annu. Rev. Biochem. 57 (1988) 701–754. [DOI] [PMID: 3052288]
2.  Strauss, E.G., De Groot, R.J., Levinson, R. and Strauss, J.H. Identification of the active site residues in the nsP2 proteinase of Sindbis virus. Virology 191 (1992) 932–940. [PMID: 1448929]
3.  Tong, L., Wengler, G. and Rossmann, M.G. Refined structure of Sindbis virus core protein and comparison with other chymotrypsin-like serine proteinase structures. J. Mol. Biol. 230 (1993) 228–247. [DOI] [PMID: 8450538]
[EC 3.4.21.90 created 1995]
 
 
EC 3.4.21.91     
Accepted name: flavivirin
Reaction: Selective hydrolysis of -Xaa-Xaa┼Yaa- bonds in which each of the Xaa can be either Arg or Lys and Yaa can be either Ser or Ala
Other name(s): Yellow fever virus (flavivirus) protease; NS2B-3 proteinase
Comments: Known from classical flaviviruses (yellow fever, dengue fever). The functional viral peptidase is part of the NS2B protein. Catalytic His, Asp and Ser residues are arranged as in chymotrypsin, but flavivrin is the type example of peptidase family S7.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 154215-26-6
References:
1.  Chambers, T.J., Hahn, C.S., Galler, R. and Rice, C.M. Flavivirus genome organization, expression, and replication. Annu. Rev. Microbiol. 44 (1990) 649–688. [DOI] [PMID: 2174669]
2.  Cahour, A., Falgout, B. and Lai, C.-J. Cleavage of the dengue virus polyprotein at the NS3/NS4A and NS4B/NS5 junctions is mediated by viral protease NS2B-NS3, whereas NS4A/NS4B may be processed by a cellular protease. J. Virol. 66 (1992) 1535–1542. [PMID: 1531368]
3.  Lin, C., Amberg, S.M., Chambers, T.J. and Rice, C.M. Cleavage at a novel site in the NS4A region by the yellow fever virus NS2B-3 proteinase is a prerequisite for processing at the downstream 4A/4B signalase site. J. Virol. 67 (1993) 2327–2335. [PMID: 8445732]
[EC 3.4.21.91 created 1995]
 
 
EC 3.4.21.92     
Accepted name: endopeptidase Clp
Reaction: Hydrolysis of proteins to small peptides in the presence of ATP and Mg2+. α-Casein is the usual test substrate. In the absence of ATP, only oligopeptides shorter than five residues are hydrolysed (such as succinyl-Leu-Tyr┼NHMec; and Leu-Tyr-Leu┼Tyr-Trp, in which cleavage of the -Tyr┼Leu- and -Tyr┼Trp bonds also occurs)
Other name(s): endopeptidase Ti; caseinolytic protease; protease Ti; ATP-dependent Clp protease; endopeptidase Ti; caseinolytic protease; ClpP; Clp protease
Comments: An enzyme from bacteria that contains subunits of two types, ClpP, with peptidase activity, and ClpA, with ATPase activity. The ClpAP complex, which displays ATP-dependent endopeptidase activity, has the composition (ClpP14ClpA6)2 [4]. ClpP is the type example of peptidase family S14
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 110910-59-3
References:
1.  Gottesman, S., Clark, W.P. and Maurizi, M.R. The ATP-dependent Clp protease of Escherichia coli. Sequence of clpA and identification of a Clp-specific substrate. J. Biol. Chem. 265 (1990) 7886–7893. [PMID: 2186030]
2.  Maurizi, M.R., Clark, W.P., Katayama, Y., Rudikoff, S., Pumphrey, J., Bowers, B. and Gottesman, S. Sequence and structure of Clp P, the proteolytic component of the ATP-dependent Clp protease of Escherichia coli. J. Biol. Chem. 265 (1990) 12536–12545. [PMID: 2197275]
3.  Maurizi, M.R., Thompson, M.W., Singh, S.K. and Kim, S.-H. Endopeptidase Clp: the ATP-dependent Clp protease from Escherichia coli. Methods Enzymol. 244 (1994) 314–331. [DOI] [PMID: 7845217]
4.  Kessel, M. , Maurizi,M.R., Kim, B., Kocsis, E., Trus, B., Singh, S.K. and Steven, A.C. Homology in structural organization between E. coli ClpAP protease and the eukaryotic 26 S proteasome. J. Mol. Biol. 250 (1995) 587–594. [DOI] [PMID: 7623377]
[EC 3.4.21.92 created 1996]
 
 
EC 3.4.21.93     
Accepted name: proprotein convertase 1
Reaction: Release of protein hormones, neuropeptides and renin from their precursors, generally by hydrolysis of -Lys-Arg┼ bonds
Other name(s): prohormone convertase 3; neuroendocrine convertase 1; PC1
Comments: A Ca2+-dependent enzyme, maximally active at about pH 5.5. Substrates include pro-opiomelanocortin, prorenin, proenkephalin, prodynorphin, prosomatostatin and proinsulin. Unlike prohormone convertase 2, does not hydrolyse proluteinizing-hormone-releasing-hormone. Unusually, processing of prodynorphin occurs at a bond in which P2 is Thr. Present in the regulated secretory pathway of neuroendocrine cells, commonly acting co-operatively with prohormone convertase 2. In peptidase family S8 (subtilisin family)
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 99676-46-7
References:
1.  Seidah, N.G., Gaspar, L., Mion, P., Marcinkiewicz, M., Mbikay, M. and Chrétien, M. cDNA sequence of two distinct pituitary proteins homologous to Kex2 and furin gene products: tissue-specific mRNAs encoding candidates for pro-hormone processing proteinases. DNA Cell Biol. 9 (1990) 415–424. [DOI] [PMID: 2169760]
2.  Smeekens, S.P., Avruch, A.S., LaMendola, J., Chan, S.J. and Steiner, D.F. Identification of a cDNA encoding a second putative prohormone convertase related to PC2 in AtT20 cells and islets of Langerhans. Proc. Natl. Acad. Sci. USA 88 (1991) 340–344. [DOI] [PMID: 1988934]
3.  Steiner, D.F., Smeekens, S.P., Ohagi, S. and Chan, S.J. The new enzymology of precursor processing endoproteases. J. Biol. Chem. 267 (1992) 23435–23438. [PMID: 1429684]
4.  Seidah, N.G. and Chrétien, M. Pro-protein convertases of the subtilisin/kexin family. Methods Enzymol. 244 (1994) 175–188. [DOI] [PMID: 7845206]
5.  Jean, F., Basak, A., Dimaio, J., Seidah, N.G. and Lazure, C. An internally quenched fluorogenic substrate of prohormone convertase 1 and furin leads to a potent prohormone convertase inhibitor. Biochem. J. 307 (1995) 689–695. [PMID: 7741698]
[EC 3.4.21.93 created 1996]
 
 
EC 3.4.21.94     
Accepted name: proprotein convertase 2
Reaction: Release of protein hormones and neuropeptides from their precursors, generally by hydrolysis of -Lys-Arg┼ bonds
Other name(s): neuroendocrine convertase 2; PC2
Comments: A Ca2+-dependent enzyme, maximally active at about pH 5.5. Specificity is broader than that of prohormone convertase 1. Substrates include pro-opiomelanocortin, proenkephalin, prodynorphin, proglucagon, proinsulin and proluteinizing-hormone-releasing-hormone. Does not hydrolyse prorenin or prosomatostatin, however. Unusually, processing of prodynorphin occurs at a bond in which P2 is Thr. Present in the regulated secretory pathway of neuroendocrine cells, commonly acting co-operatively with prohormone convertase 1. In peptidase family S8 (subtilisin family)
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, CAS registry number: 388092-42-0
References:
1.  Seidah, N.G., Gaspar, L., Mion, P., Marcinkiewicz, M., Mbikay, M. and Chrétien, M. cDNA sequence of two distinct pituitary proteins homologous to Kex2 and furin gene products: tissue-specific mRNAs encoding candidates for pro-hormone processing proteinases. DNA Cell Biol. 9 (1990) 415–424. [DOI] [PMID: 2169760]
2.  Smeekens, S.P. and Steiner, D.F. Identification of a human insulinoma cDNA encoding a novel mammalian protein structurally related to the yeast dibasic processing protease Kex2. J. Biol. Chem. 265 (1990) 2997–3000. [PMID: 2154467]
3.  Rouillé, Y., Westermark, G., Martin, S.K. and Steiner, D.F. Proglucagon is processed to glucagon by prohormone convertase PC2 in alphaTC1-6 cells. Proc. Natl. Acad. Sci. USA 91 (1994) 3242–3246. [DOI] [PMID: 8159732]
4.  Seidah, N.G. and Chrétien, M. Pro-protein convertases of the subtilisin/kexin family. Methods Enzymol. 244 (1994) 175–188. [DOI] [PMID: 7845206]
[EC 3.4.21.94 created 1996]
 
 
EC 3.4.21.95     
Accepted name: snake venom factor V activator
Reaction: Fully activates human clotting factor V by a single cleavage at the Trp-Tyr-Leu-Arg1545┼Ser-Asn-Asn-Gly bond. Cattle, but not rabbit, factor V is cleaved, and no other proteins of the clotting system are attacked. Esterase activity is observed on Bz-Arg-OEt and Tos-Arg-OMe, and amidase activity on Phe-pipecolyl-Arg-NHPhNO2
Comments: Known from venom of Vipera russelli. Inhibited by di-isopropyl fluorophosphate, unlike the metallopeptidase russellysin (EC 3.4.24.58) that is specific for factor X [1]. In peptidase family S1 (trypsin family) [2].
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 471269-12-2, 123757-15-3, 123757-16-4, 123757-17-5, 123757-18-6
References:
1.  Kisiel, W. and Canfield, W. M. Snake venom proteases that activate blood-coagulation factor V. Methods Enzymol. 80 (1981) 275–285. [PMID: 7043192]
2.  Tokunaga, F., Nagasawa, K., Tamura, S., Miyata, T., Iwanaga, S. and Kisiel, W. The factor V-activating enzyme (RVV-V) from Russell's viper venom. Identification of isoproteins RVV-Vα, -Vβ and -Vγ and their complete amino acid sequences. J. Biol. Chem. 263 (1988) 17417–17481. [PMID: 3053712]
[EC 3.4.21.95 created 1997]
 
 
EC 3.4.21.97     
Accepted name: assemblin
Reaction: Cleaves -Ala┼Ser- and -Ala┼Ala- bonds in the scaffold protein
Comments: Involved in the breakdown of the scaffold protein during the late stages of assembly of the herpes-virus virion. Inhibited by diisopropyl fluorophosphate. Type example of peptidase family S21. Catalytic residues are His, Ser, His, a combination not known for any other peptidase, and the protein fold also is unique. Known from herpes viruses of several types, cytomegalovirus, Epstein-Barr virus and human herpesvirus 3
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 139691-88-6
References:
1.  Chen, P., Tsuge, H., Almassy, R.J., Gribskov, C.L., Katoh, S., Vanderpool, D.L., Margosiak, S.A., Pinko, C., Matthews, D.A. and Kan, C.C. Structure of the human cytomegalovirus protease catalytic domain reveals a novel serine protease fold and catalytic triad. Cell 86 (1996) 477–483. [DOI] [PMID: 8797829]
2.  Darke, P.L. Herpesvirus assemblin. In: Barrett, A.J., Rawlings, N.D. and Woessner, J.F. (Eds), Handbook of Proteolytic Enzymes, Academic Press, London, 1998, pp. 470–472.
[EC 3.4.21.97 created 2000]
 
 
EC 3.4.21.98     
Accepted name: hepacivirin
Reaction: Hydrolysis of four peptide bonds in the viral precursor polyprotein, commonly with Asp or Glu in the P6 position, Cys or Thr in P1 and Ser or Ala in P1′
Other name(s): Cpro-2; hepatitis C virus NS3 serine proteinase; NS3-4A serine proteinase complex
Comments: Encoded by the genome of the viruses of the hepatitis C group, and contributes to the maturation of the precursor polyproteins. The enzyme is greatly activated by binding of the 54-residue NS4A ’cofactor’ protein also derived from the viral polyprotein. Type example of peptidase family S29. The crystallographic structure shows a chymotrypsin-like fold.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 149885-80-3
References:
1.  Kim, J.L., Morgenstern, K.A., Lin, C., Fox, T., Dwyer, M.D., Landro, J.A., Chambers, S.P., Markland, W., Lepre, C.A., O'Malley, E.T., Harbeson, S.L., Rice, C.M., Murcko, M.A., Caron, P.R. and Thomson, J.A. Crystal structure of the hepatitis C virus NS3 protease domain complexed with a synthetic NS4A cofactor peptide. Cell 87 (1996) 343–355. [DOI] [PMID: 8861917]
2.  Rice, C.M. Hepatitis C virus polyprotein peptidase. In: Barrett, A.J., Rawlings, N.D. and Woessner, J.F. (Eds), Handbook of Proteolytic Enzymes, Academic Press, London, 1998, pp. 272–277.
[EC 3.4.21.98 created 2000]
 
 
EC 3.4.21.99     
Accepted name: spermosin
Reaction: Hydrolyses arginyl bonds, preferably with Pro in the P2 position
Comments: The enzyme from the ascidian (Prochordate) Halocynthia roretzi is localized in the sperm head, and released during sperm activation. A proline-rich region is involved in binding to the vitelline coat of the egg. Belongs in peptidase family S1 (trypsin family).
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, CAS registry number: 89925-67-7
References:
1.  Sawada, H., Yokosawa, H. and Ishii, S. Purification and characterization of two types of trypsin-like enzymes from sperm of the ascidian (Prochordata) Halocynthia roretzi. Evidence for the presence of spermosin, a novel acrosin-like enzyme. J. Biol. Chem. 259 (1984) 2900–2904. [PMID: 6365918]
2.  Sawada, H., Yokosawa, H., Someno, T., Saino, T. and Ishii, S. Evidence for the participation of two sperm proteases, spermosin and acrosin, in fertilization of the ascidian, Halocynthia roretzi: inhibitory effects of leupeptin analogs on enzyme activities and fertilization. Dev. Biol. 105 (1984) 246–249. [DOI] [PMID: 6381175]
3.  Sawada, H., Iwasaki, K., Kihara-Negishi, F., Ariga, H. and Yokosawa, H. Localization, expression, and the role in fertilization of spermosin, an ascidian sperm trypsin-like protease. Biochem. Biophys. Res. Commun. 222 (1996) 499–504. [DOI] [PMID: 8670234]
4.  Sawada, H. and Someno, T. Substrate specificity of ascidian sperm trypsin-like proteases, spermosin and acrosin. Mol. Reprod. Dev. 45 (1996) 240–243. [DOI] [PMID: 8914083]
[EC 3.4.21.99 created 2001]
 
 
EC 3.4.21.102     
Accepted name: C-terminal processing peptidase
Reaction: The enzyme shows specific recognition of a C-terminal tripeptide, Xaa-Yaa-Zaa, in which Xaa is preferably Ala or Leu, Yaa is preferably Ala or Tyr, and Zaa is preferably Ala, but then cleaves at a variable distance from the C-terminus. A typical cleavage is -Ala-Ala┼Arg-Ala-Ala-Lys-Glu-Asn-Tyr-Ala-Leu-Ala-Ala. In the plant chloroplast, the enzyme removes the C-terminal extension of the D1 polypeptide of photosystem II
Other name(s): CtpA gene product (Synechocystis sp.); photosystem II D1 protein processing peptidase; protease Re; tail-specific protease; Tsp protease
Comments: Proteolytic processing of the D1 protein of photosystem II is necessary to allow the light-driven assembly of the tetranuclear manganese cluster, which is responsible for photosynthetic water oxidation. The recognition of the substrate is mediated by a PDZ domain, a small protein module that promotes protein-protein interactions by binding to internal or C-terminal sequences of their partner proteins. Type example of peptidase family S41.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, CAS registry number: 216484-75-2, 92480-11-0
References:
1.  Keiler, K.C. and Sauer, R.T. Tsp protease. In: Barrett, A.J., Rawlings, N.D. and Woessner, J.F. (Eds), Handbook of Proteolytic Enzymes, Handbook of Proteolytic Enzymes, London, 1998, pp. 460–461.
2.  Beebe, K.D., Shin, J.N., Peng, J., Chaudhury, C., Khera, J. and Pei, D.H. Substrate recognition through a PDZ domain in tail-specific protease. Biochemistry 39 (2000) 3149–3155. [DOI] [PMID: 10715137]
3.  Liao, D.I., Qian, J., Chisholm, D.A., Jordan, D.B. and Diner, B.A. Crystal structures of the photosystem II D1 C-terminal processing protease. Nat. Struct. Biol. 7 (2000) 749–753. [DOI] [PMID: 10966643]
[EC 3.4.21.102 created 2001]
 
 
EC 3.4.21.103     
Accepted name: physarolisin
Reaction: Milk clotting activity. Preferential cleavage of Gly8┼Ser in B chain of insulin most rapidly, followed by Leu11┼Val, Cys(SO3H)19┼Gly and Phe24┼Phe. No action on Ac-Phe-Tyr(I)2.
Other name(s): Dictyostelium discoideum aspartic proteinase; Dictyostelium discoideum aspartic proteinase E; Physarum flavicomum aspartic proteinase; Physarum polycephalum acid proteinase; Physarum aspartic proteinase; physaropepsin
Comments: Belongs in peptidase family S53. From the slime mold Physarum polycephalum. Is not inhibited by pepstatin, but is blocked by methyl 2-diazoacetamidohexanoate. Closely similar enzymes are found in Dictyostelium discoideum and P. flavicomum. Formerly included in EC 3.4.23.6.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, CAS registry number: 94949-28-7
References:
1.  Henney, H.R. and Tavana, G. Purification and some properties of an intracellular acid (carboxyl) proteinase from differentiating haploid cells of Physarum flavicomum. Exp. Mycol. 6 (1982) 161–170.
2.  Murakami-Murofushi, K., Hiratsuka, A. and Ohta, J. A novel acid protease from haploid amoebae of Physarum polycephalum, and its changes during mating and subsequent differentiation into diploid plasmodia. Cell Struct. Funct. 9 (1984) 311–315.
3.  North, M.J. and Whyte, A. Purification and characterization of two acid proteinases from Dictyostelium discoideum. J. Gen. Microbiol. 130 (1984) 123–134.
4.  Wlodawer, A., Li, M., Gustchina, A., Oyama, H., Dunn, B.M. and Oda, K. Structural and enzymatic properties of the sedolisin family of serine-carboxyl peptidases. Acta Biochim. Pol. 50 (2003) 81–102. [DOI] [PMID: 12673349]
5.  Nishii, W., Ueki, T., Miyashita, R., Kojima, M., Kim, Y.T., Sasaki, N., Murakami-Murofushi, K. and Takahashi, K. Structural and enzymatic characterization of physarolisin (formerly physaropepsin) proves that it is a unique serine-carboxyl proteinase. Biochem. Biophys. Res. Commun. 301 (2003) 1023–1029. [DOI] [PMID: 12589815]
[EC 3.4.21.103 created 1992 as EC 3.4.23.27 (EC 3.4.23.6 created 1992 (EC 3.4.23.6 created 1961 as EC 3.4.4.17, transferred 1972 to EC 3.4.23.6, modified 1981 [EC 3.4.23.7, EC 3.4.23.8, EC 3.4.23.9, EC 3.4.23.10, EC 3.4.99.1, EC 3.4.99.15 and EC 3.4.99.25 all created 1972 and incorporated 1978], part incorporated 1992), transferred 2003 to EC 3.4.21.103]
 
 
EC 3.4.21.104     
Accepted name: mannan-binding lectin-associated serine protease-2
Reaction: Selective cleavage after Arg223 in complement component C2 (-Ser-Leu-Gly-Arg┼Lys-Ile-Gln-Ile) and after Arg76 in complement component C4 (-Gly-Leu-Gln-Arg┼Ala-Leu-Glu-Ile)
Other name(s): MASP-2; MASP2; MBP-associated serine protease-2; mannose-binding lectin-associated serine protease-2; p100; mannan-binding lectin-associated serine peptidase 2
Comments: Mannan-binding lectin (MBL) recognizes patterns of neutral carbohydrates, such as mannose and N-acetylglucosamine, on a wide range of microbial surfaces and is able to initiate activation of the lectin pathway of complement [7]. This enzyme displays C1s-like esterolytic activity (cf. EC 3.4.21.42, complement subcomponent C1s). It also cleaves C4 and C2 with efficiencies that are relatively higher than those of EC 3.4.21.42 [3]. Belongs in peptidase family S1A.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, PDB, CAS registry number: 214915-16-9
References:
1.  Matsushita, M. and Fujita, T. Activation of the classical complement pathway by mannose-binding protein in association with a novel C1s-like serine protease. J. Exp. Med. 176 (1992) 1497–1502. [PMID: 1460414]
2.  Thiel, S., Vorup-Jensen, T., Stover, C.M., Schwaeble, W., Laursen, S.B., Poulsen, K., Willis, A.C., Eggleton, P., Hansen, S., Holmskov, U., Reid, K.B. and Jensenius, J.C. A second serine protease associated with mannan-binding lectin that activates complement. Nature 386 (1997) 506–510. [DOI] [PMID: 9087411]
3.  Rossi, V., Cseh, S., Bally, I., Thielens, N.M., Jensenius, J.C. and Arlaud, G.J. Substrate specificities of recombinant mannan-binding lectin-associated serine proteases-1 and -2. J. Biol. Chem. 276 (2001) 40880–40887. [DOI] [PMID: 11527969]
4.  Ambrus, G., Gal, P., Kojima, M., Szilagyi, K., Balczer, J., Antal, J., Graf, L., Laich, A., Moffatt, B.E., Schwaeble, W., Sim, R.B. and Zavodszky, P. Natural substrates and inhibitors of mannan-binding lectin-associated serine protease-1 and -2: a study on recombinant catalytic fragments. J. Immunol. 170 (2003) 1374–1382. [DOI] [PMID: 12538697]
5.  Harmat, V., Gal, P., Kardos, J., Szilagyi, K., Ambrus, G., Vegh, B., Naray-Szabo, G. and Zavodszky, P. The structure of MBL-associated serine protease-2 reveals that identical substrate specificities of C1s and MASP-2 are realized through different sets of enzyme-substrate interactions. J. Mol. Biol. 342 (2004) 1533–1546. [DOI] [PMID: 15364579]
6.  Chen, C.B. and Wallis, R. Two mechanisms for mannose-binding protein modulation of the activity of its associated serine proteases. J. Biol. Chem. 279 (2004) 26058–26065. [DOI] [PMID: 15060079]
7.  Teillet, F., Dublet, B., Andrieu, J.P., Gaboriaud, C., Arlaud, G.J. and Thielens, N.M. The two major oligomeric forms of human mannan-binding lectin: chemical characterization, carbohydrate-binding properties, and interaction with MBL-associated serine proteases. J. Immunol. 174 (2005) 2870–2877. [DOI] [PMID: 15728497]
[EC 3.4.21.104 created 2005]
 
 
EC 3.4.21.105     
Accepted name: rhomboid protease
Reaction: Cleaves type-1 transmembrane domains using a catalytic dyad composed of serine and histidine that are contributed by different transmembrane domains
Comments: These endopeptidases are multi-spanning membrane proteins. Their catalytic site is embedded within the membrane and they cleave type-1 transmembrane domains. A catalytic dyad is involved in proteolysis rather than a catalytic triad, as was thought previously [14]. They are important for embryo development in Drosophila melanogaster. Rhomboid is a key regulator of EGF receptor signalling and is responsible for cleaving Spitz, the main ligand of the Drosophila EGF receptor pathway. Belongs in peptidase family S54. Parasite-encoded rhomboid enzymes are also important for invasion of host cells by Toxoplasma and the malaria parasite. Rhomboids are widely conserved from bacteria to archaea to humans [9,13].
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, PDB, CAS registry number: 713145-02-9
References:
1.  Urban, S. and Wolfe, M.S. Reconstitution of intramembrane proteolysis in vitro reveals that pure rhomboid is sufficient for catalysis and specificity. Proc. Natl. Acad. Sci. USA 102 (2005) 1883–1888. [DOI] [PMID: 15684070]
2.  Brossier, F., Jewett, T.J., Sibley, L.D. and Urban, S. A spatially localized rhomboid protease cleaves cell surface adhesins essential for invasion by Toxoplasma. Proc. Natl. Acad. Sci. USA 102 (2005) 4146–4151. [DOI] [PMID: 15753289]
3.  Herlan, M., Bornhovd, C., Hell, K., Neupert, W. and Reichert, A.S. Alternative topogenesis of Mgm1 and mitochondrial morphology depend on ATP and a functional import motor. J. Cell Biol. 165 (2004) 167–173. [DOI] [PMID: 15096522]
4.  Pascall, J.C. and Brown, K.D. Intramembrane cleavage of ephrinB3 by the human rhomboid family protease, RHBDL 2. Biochem. Biophys. Res. Commun. 317 (2004) 244–252. [DOI] [PMID: 15047175]
5.  Sik, A., Passer, B.J., Koonin, E.V. and Pellegrini, L. Self-regulated cleavage of the mitochondrial intramembrane-cleaving protease PARL yields Pβ, a nuclear-targeted peptide. J. Biol. Chem. 279 (2004) 15323–15329. [DOI] [PMID: 14732705]
6.  Urban, S. and Freeman, M. Substrate specificity of Rhomboid intramembrane proteases is governed by helix-breaking residues in the substrate transmembrane domain. Mol. Cell 11 (2003) 1425–1434. [DOI] [PMID: 12820957]
7.  Herlan, M., Vogel, F., Bornhovd, C., Neupert, W. and Reichert, A.S. Processing of Mgm1 by the rhomboid-type protease Pcp1 is required for maintenance of mitochondrial morphology and of mitochondrial DNA. J. Biol. Chem. 278 (2003) 27781–27788. [DOI] [PMID: 12707284]
8.  McQuibban, G.A., Saurya, S. and Freeman, M. Mitochondrial membrane remodelling regulated by a conserved rhomboid protease. Nature 423 (2003) 537–541. [DOI] [PMID: 12774122]
9.  Koonin, E.V., Makarova, K.S., Rogozin, I.B., Davidovic, L., Letellier, M.C. and Pellegrini, L. The rhomboids: a nearly ubiquitous family of intramembrane serine proteases that probably evolved by multiple ancient horizontal gene transfers. Genome Biol. 4 (2003) R19. [DOI] [PMID: 12620104]
10.  Urban, S. and Freeman, M. Intramembrane proteolysis controls diverse signalling pathways throughout evolution. Curr. Opin. Genet. Dev. 12 (2002) 512–518. [DOI] [PMID: 12200155]
11.  Urban, S., Schlieper, D. and Freeman, M. Conservation of intramembrane proteolytic activity and substrate specificity in prokaryotic and eukaryotic Rhomboids. Curr. Biol. 12 (2002) 1507–1512. [DOI] [PMID: 12225666]
12.  Urban, S., Lee, J.R. and Freeman, M. A family of Rhomboid intramembrane proteases activates all Drosophila membrane-tethered EGF-like ligands. EMBO J. 21 (2002) 4277–4286. [DOI] [PMID: 12169630]
13.  Urban, S., Lee, J.R. and Freeman, M. Drosophila Rhomboid-1 defines a family of putative intramembrane serine proteases. Cell 107 (2001) 173–182. [DOI] [PMID: 11672525]
14.  Lemberg, M.K., Menendez, J., Misik, A., Garcia, M., Koth, C.M. and Freeman, M. Mechanism of intramembrane proteolysis investigated with purified rhomboid proteases. EMBO J. 24 (2005) 464–472. [DOI] [PMID: 15616571]
15.  Wang, Y., Zhang, Y. and Ha, Y. Crystal structure of a rhomboid family intramembrane protease. Nature 444 (2006) 179–180. [DOI] [PMID: 17051161]
[EC 3.4.21.105 created 2005]
 
 
EC 3.4.21.106     
Accepted name: hepsin
Reaction: Cleavage after basic amino-acid residues, with Arg strongly preferred to Lys
Comments: This type-II membrane-associated serine peptidase has been implicated in cell growth and development [1,3]. The enzyme has been shown to activate blood coagulation factor VII by cleavage of the Arg152┼Ile153 peptide bound in BHK cells, thus indicating a possible role in the initiation of blood coagulation [2]. There is no cleavage after aromatic or aliphatic residues [1]. The occupancy of the S2 site is an absolute requirement for catalysis and a basic residue at that site is preferred to an aliphatic residue. The nature of the residue at S3 also affects hydrolysis, with Gln being much more favourable than Ala [1]. Belongs in peptidase family S1A.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, PDB, CAS registry number: 112398-23-9
References:
1.  Zhukov, A., Hellman, U. and Ingelman-Sundberg, M. Purification and characterization of hepsin from rat liver microsomes. Biochim. Biophys. Acta 1337 (1997) 85–95. [DOI] [PMID: 9003440]
2.  Kazama, Y., Hamamoto, T., Foster, D.C. and Kisiel, W. Hepsin, a putative membrane-associated serine protease, activates human factor VII and initiates a pathway of blood coagulation on the cell surface leading to thrombin formation. J. Biol. Chem. 270 (1995) 66–72. [DOI] [PMID: 7814421]
3.  Torres-Rosado, A., O'Shea, K.S., Tsuji, A., Chou, S.H. and Kurachi, K. Hepsin, a putative cell-surface serine protease, is required for mammalian cell growth. Proc. Natl. Acad. Sci. USA 90 (1993) 7181–7185. [DOI] [PMID: 8346233]
[EC 3.4.21.106 created 2006]
 
 
EC 3.4.21.107     
Accepted name: peptidase Do
Reaction: Acts on substrates that are at least partially unfolded. The cleavage site P1 residue is normally between a pair of hydrophobic residues, such as Val┼Val
Other name(s): DegP; DegP protease; HtrA; high temperature requirement protease A; HrtA heat shock protein; protease Do; Do protease
Comments: This serine endopeptidase is essential for the clearance of denatured or aggregated proteins from the inner-membrane and periplasmic space in Escherichia coli. Natural substrates of the enzyme include colicin A lysis protein, pilin subunits and MalS from E. coli [3]. The enzyme has weak peptidase activity with casein and other non-native substrates [3]. The peptidase acts as a chaperone at low temperatures but switches to a peptidase (heat shock protein) at higher temperatures [1,6]. Molecular chaperones and peptidases control the folded state of proteins by recognizing hydrophobic stretches of polypeptide that become exposed by misfolding or unfolding. They then bind these hydrophobic substrates to prevent aggregation or assist in protein refolding. If attempts at refolding fail, then irreversibly damaged proteins are degraded by peptidases such as this enzyme [6]. Belongs in peptidase family S1C.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, CAS registry number: 161108-11-8
References:
1.  Lipinska, B., Zylicz, M. and Georgopoulos, C. The HtrA (DegP) protein, essential for Escherichia coli survival at high temperatures, is an endopeptidase. J. Bacteriol. 172 (1990) 1791–1797. [DOI] [PMID: 2180903]
2.  Seol, J.H., Woo, S.K., Jung, E.M., Yoo, S.J., Lee, C.S., Kim, K.J., Tanaka, K., Ichihara, A., Ha, D.B. and Chung, C.H. Protease Do is essential for survival of Escherichia coli at high temperatures: its identity with the htrA gene product. Biochem. Biophys. Res. Commun. 176 (1991) 730–736. [DOI] [PMID: 2025286]
3.  Jones, C.H., Dexter, P., Evans, A.K., Liu, C., Hultgren, S.J. and Hruby, D.E. Escherichia coli DegP protease cleaves between paired hydrophobic residues in a natural substrate: the PapA pilin. J. Bacteriol. 184 (2002) 5762–5771. [DOI] [PMID: 12270835]
4.  Swamy, K.H., Chung, C.H. and Goldberg, A.L. Isolation and characterization of protease Do from Escherichia coli, a large serine protease containing multiple subunits. Arch. Biochem. Biophys. 224 (1983) 543–554. [DOI] [PMID: 6347072]
5.  Pallen, M.J. and Wren, B.W. The HtrA family of serine proteases. Mol. Microbiol. 26 (1997) 209–221. [DOI] [PMID: 9383148]
6.  Krojer, T., Garrido-Franco, M., Huber, R., Ehrmann, M. and Clausen, T. Crystal structure of DegP (HtrA) reveals a new protease-chaperone machine. Nature 416 (2002) 455–459. [DOI] [PMID: 11919638]
[EC 3.4.21.107 created 2006]
 
 
EC 3.4.21.108     
Accepted name: HtrA2 peptidase
Reaction: Cleavage of non-polar aliphatic amino-acids at the P1 position, with a preference for Val, Ile and Met. At the P2 and P3 positions, Arg is selected most strongly with a secondary preference for other hydrophilic residues
Other name(s): high temperature requirement protein A2; HtrA2; Omi stress-regulated endoprotease; serine proteinase OMI; HtrA2 protease; OMI/HtrA2 protease; HtrA2/Omi; Omi/HtrA2
Comments: This enzyme is upregulated in mammalian cells in response to stress induced by both heat shock and tunicamycin treatment [4]. It can induce apoptosis in a caspase-independent manner through its peptidase activity and in a caspase-dependent manner by disrupting the interaction between caspase and the inhibitor of apoptosis (IAP) [3]. Belongs in peptidase family S1C.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, PDB
References:
1.  Srinivasula, S.M., Gupta, S., Datta, P., Zhang, Z., Hegde, R., Cheong, N., Fernandes-Alnemri, T. and Alnemri, E.S. Inhibitor of apoptosis proteins are substrates for the mitochondrial serine protease Omi/HtrA2. J. Biol. Chem. 278 (2003) 31469–31472. [DOI] [PMID: 12835328]
2.  Savopoulos, J.W., Carter, P.S., Turconi, S., Pettman, G.R., Karran, E.H., Gray, C.W., Ward, R.V., Jenkins, O. and Creasy, C.L. Expression, purification, and functional analysis of the human serine protease HtrA2. Protein. Expr. Purif. 19 (2000) 227–234. [DOI] [PMID: 10873535]
3.  Martins, L.M., Turk, B.E., Cowling, V., Borg, A., Jarrell, E.T., Cantley, L.C. and Downward, J. Binding specificity and regulation of the serine protease and PDZ domains of HtrA2/Omi. J. Biol. Chem. 278 (2003) 49417–49427. [DOI] [PMID: 14512424]
4.  Gray, C.W., Ward, R.V., Karran, E., Turconi, S., Rowles, A., Viglienghi, D., Southan, C., Barton, A., Fantom, K.G., West, A., Savopoulos, J., Hassan, N.J., Clinkenbeard, H., Hanning, C., Amegadzie, B., Davis, J.B., Dingwall, C., Livi, G.P. and Creasy, C.L. Characterization of human HtrA2, a novel serine protease involved in the mammalian cellular stress response. Eur. J. Biochem. 267 (2000) 5699–5710. [DOI] [PMID: 10971580]
5.  Li, W., Srinivasula, S.M., Chai, J., Li, P., Wu, J.W., Zhang, Z., Alnemri, E.S. and Shi, Y. Structural insights into the pro-apoptotic function of mitochondrial serine protease HtrA2/Omi. Nat. Struct. Biol. 9 (2002) 436–441. [DOI] [PMID: 11967569]
[EC 3.4.21.108 created 2006]
 
 
EC 3.4.21.109     
Accepted name: matriptase
Reaction: Cleaves various synthetic substrates with Arg or Lys at the P1 position and prefers small side-chain amino acids, such as Ala and Gly, at the P2 position
Other name(s): serine protease 14; membrane-type serine protease 1; MT-SP1; prostamin; serine protease TADG-15; tumor-associated differentially-expressed gene 15 protein; ST14; breast cancer 80 kDa protease; epithin; serine endopeptidase SNC19
Comments: This trypsin-like integral-membrane serine peptidase has been implicated in breast cancer invasion and metastasis [1,2]. The enzyme can activate hepatocyte growth factor/scattering factor (HGF/SF) by cleavage of the two-chain form at an Arg residue to give active α- and β-HGF, but It does not activate plasminogen, which shares high homology with HGF [1]. The enzyme can also activate urokinase plasminogen activator (uPA), which initiates the matrix-degrading peptidase cascade [1,2]. Belongs in peptidase family S1A.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, PDB, CAS registry number: 241475-96-7
References:
1.  Lee, S.L., Dickson, R.B. and Lin, C.Y. Activation of hepatocyte growth factor and urokinase/plasminogen activator by matriptase, an epithelial membrane serine protease. J. Biol. Chem. 275 (2000) 36720–36725. [DOI] [PMID: 10962009]
2.  Lin, C.Y., Anders, J., Johnson, M., Sang, Q.A. and Dickson, R.B. Molecular cloning of cDNA for matriptase, a matrix-degrading serine protease with trypsin-like activity. J. Biol. Chem. 274 (1999) 18231–18236. [DOI] [PMID: 10373424]
[EC 3.4.21.109 created 2006]
 
 
EC 3.4.21.111     
Accepted name: aqualysin 1
Reaction: Exhibits low specificity towards esters of amino acids with small hydrophobic or aromatic residues at the P1 position
Other name(s): caldolysin
Comments: This enzyme from the extreme thermophile, Thermus aquaticus, is an alkaline serine peptidase. It has three subsites, S1, S2, and S3, in the substrate binding site. The preferred amino acids at the S1 site are Ala and Phe, at the S2 site are Ala and norleucine and at the S3 site are Phe and Ile [3]. These specificities are similar to those of EC 3.4.21.64 (peptidase K) and EC 3.4.21.62 (subtilisin BPN′) [3]. The enzyme displays broad specificity for cleavage of insulin B-chain and hydrolyses elastin substrates such as succinyl-(Ala)n-p-nitroanilide (n = 1,2,3) and some peptide esters [1,3]. Belongs in peptidase family S8A.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, CAS registry number: 88747-68-6
References:
1.  Matsuzawa, H., Tokugawa, K., Hamaoki, M., Mizoguchi, M., Taguchi, H., Terada, I., Kwon, S.T. and Ohta, T. Purification and characterization of aqualysin I (a thermophilic alkaline serine protease) produced by Thermus aquaticus YT-1. Eur. J. Biochem. 171 (1988) 441–447. [DOI] [PMID: 3162211]
2.  Tanaka, T., Matsuzawa, H., Kojima, S., Kumagai, I., Miura, K. and Ohta, T. P1 specificity of aqualysin I (a subtilisin-type serine protease) from Thermus aquaticus YT-1, using P1-substituted derivatives of Streptomyces subtilisin inhibitor. Biosci. Biotechnol. Biochem. 62 (1998) 2035–2038. [PMID: 9882104]
3.  Tanaka, T., Matsuzawa, H. and Ohta, T. Substrate specificity of aqualysin I, a bacterial thermophilic alkaline serine protease from Thermus aquaticus YT-1: Comparison with proteinase K, subtilisin BPN′ and subtilisin Carlsberg. Biosci. Biotechnol. Biochem. 62 (1998) 2161–2165. [PMID: 27393587]
[EC 3.4.21.111 created 2006]
 
 
EC 3.4.21.112     
Accepted name: site-1 protease
Reaction: Processes precursors containing basic and hydrophobic/aliphatic residues at P4 and P2, respectively, with a relatively relaxed acceptance of amino acids at P1 and P3
Other name(s): mammalian subtilisin/kexin isozyme 1; membrane-bound transcription factor site-1 protease; proprotein convertase SKI-1; proprotein convertase SKI-1/S1PPS1; S1P endopeptidase; S1P protease; site-1 peptidase; site-1 protease; SKI-1; SREBP proteinase; SREBP S1 protease; SREBP-1 proteinase; SREBP-2 proteinase; sterol regulatory element-binding protein proteinase; sterol regulatory element-binding protein site 1 protease; sterol-regulated luminal protease; subtilase SKI-1; subtilase SKI-1/S1P; subtilisin/kexin-isozyme 1
Comments: Cleaves sterol regulatory element-binding proteins (SREBPs) and thereby initiates a process by which the active fragments of the SREBPs translocate to the nucleus and activate genes controlling the synthesis and uptake of cholesterol and unsaturated fatty acids into the bloodstream [1]. The enzyme also processes pro-brain-derived neurotrophic factor and undergoes autocatalytic activation in the endoplasmic reticulum through sequential cleavages [5]. The enzyme can also process the unfolded protein response stress factor ATF6 at an Arg-His-Lys-Lys┼ site [4,8], and the envelope glycoprotein of the highly infectious Lassa virus [5,8] and Crimean Congo hemorrhagic fever virus at Arg-Arg-Lys-Lys┼ [7,8]. Belongs in peptidase family S8A.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, CAS registry number: 167140-48-9
References:
1.  Espenshade, P.J., Cheng, D., Goldstein, J.L. and Brown, M.S. Autocatalytic processing of site-1 protease removes propeptide and permits cleavage of sterol regulatory element-binding proteins. J. Biol. Chem. 274 (1999) 22795–22804. [DOI] [PMID: 10428864]
2.  Cheng, D., Espenshade, P.J., Slaughter, C.A., Jaen, J.C., Brown, M.S. and Goldstein, J.L. Secreted site-1 protease cleaves peptides corresponding to luminal loop of sterol regulatory element-binding proteins. J. Biol. Chem. 274 (1999) 22805–22812. [DOI] [PMID: 10428865]
3.  Touré, B.B., Munzer, J.S., Basak, A., Benjannet, S., Rochemont, J., Lazure, C., Chrétien, M. and Seidah, N.G. Biosynthesis and enzymatic characterization of human SKI-1/S1P and the processing of its inhibitory prosegment. J. Biol. Chem. 275 (2000) 2349–2358. [DOI] [PMID: 10644685]
4.  Ye, J., Rawson, R.B., Komuro, R., Chen, X., Dave, U.P., Prywes, R., Brown, M.S. and Goldstein, J.L. ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Mol. Cell 6 (2000) 1355–1364. [DOI] [PMID: 11163209]
5.  Lenz, O., ter Meulen, J., Klenk, H.D., Seidah, N.G. and Garten, W. The Lassa virus glycoprotein precursor GP-C is proteolytically processed by subtilase SKI-1/S1P. Proc. Natl. Acad. Sci. USA 98 (2001) 12701–12705. [DOI] [PMID: 11606739]
6.  Basak, A., Chrétien, M. and Seidah, N.G. A rapid fluorometric assay for the proteolytic activity of SKI-1/S1P based on the surface glycoprotein of the hemorrhagic fever Lassa virus. FEBS Lett. 514 (2002) 333–339. [DOI] [PMID: 11943176]
7.  Vincent, M.J., Sanchez, A.J., Erickson, B.R., Basak, A., Chretien, M., Seidah, N.G. and Nichol, S.T. Crimean-Congo hemorrhagic fever virus glycoprotein proteolytic processing by subtilase SKI-1. J. Virol. 77 (2003) 8640–8649. [DOI] [PMID: 12885882]
8.  Seidah, N.G. and Chrétien, M. Proprotein convertase SKI-1/S1P. In: Barrett, A.J., Rawlings, N.D. and Woessner, J.F. (Eds), Handbook of Proteolytic Enzymes, 2nd edn, vol. 2, Elsevier, London, 2004, pp. 1845–1847.
[EC 3.4.21.112 created 2006]
 
 
EC 3.4.21.113     
Accepted name: pestivirus NS3 polyprotein peptidase
Reaction: Leu is conserved at position P1 for all four cleavage sites. Alanine is found at position P1′ of the NS4A-NS4B cleavage site, whereas serine is found at position P1′ of the NS3-NS4A, NS4B-NS5A and NS5A-NS5B cleavage sites
Other name(s): border disease virus NS3 endopeptidase; BDV NS3 endopeptidase; bovine viral diarrhea virus NS3 endopeptidase; BVDV NS3 endopeptidase; classical swine fever virus NS3 endopeptidase; CSFV NS3 endopeptidase; p80
Comments: The polyprotein of noncytopathogenic pestiviruses is cleaved co- and post-translationally into at least 11 proteins (Npro, C, Erns, E1, E2, p7, NS2-3, NS4A, NS4B, NS5A, and NS5B) [2]. The genomes of cytopathogenic pestivirus strains express at least one additional protein, called NS3 (p80) [2]. This enzyme, which resides in the N-terminal region of NS3 (nonstructural protein 3), is essential for generation of its own C-terminus and for processing of the downstream cleavage sites, leading to the release of the pestivirus nonstructural proteins NS4A, NS4B, NS5A and NS5B [1,2]. Belongs in peptidase family S31.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, PDB
References:
1.  Wiskerchen, M. and Collett, M.S. Pestivirus gene expression: protein p80 of bovine viral diarrhea virus is a proteinase involved in polyprotein processing. Virology 184 (1991) 341–350. [PMID: 1651596]
2.  Tautz, N., Elbers, K., Stoll, D., Meyers, G. and Thiel, H.J. Serine protease of pestiviruses: determination of cleavage sites. J. Virol. 71 (1997) 5415–5422. [PMID: 9188613]
3.  Xu, J., Mendez, E., Caron, P.R., Lin, C., Murcko, M.A., Collett, M.S. and Rice, C.M. Bovine viral diarrhea virus NS3 serine proteinase: polyprotein cleavage sites, cofactor requirements, and molecular model of an enzyme essential for pestivirus replication. J. Virol. 71 (1997) 5312–5322. [PMID: 9188600]
4.  Tautz, N., Kaiser, A. and Thiel, H.J. NS3 serine protease of bovine viral diarrhea virus: characterization of active site residues, NS4A cofactor domain, and protease-cofactor interactions. Virology 273 (2000) 351–363. [DOI] [PMID: 10915606]
[EC 3.4.21.113 created 2006]
 
 
EC 3.4.21.114     
Accepted name: equine arterivirus serine peptidase
Reaction: Cleavage of (Glu/Gln)┼(Gly/Ser/Ala) in arterivirus replicase translation products ORF1a and ORF1ab
Glossary: arterivirus nsp4; equine arteritis virus serine peptidase; 3C-like serine protease; 3C-like Ser protease; 3CLSP; nonstructural protein 4 serine protease, Nsp4 serine protease; nsp4 serine protease; Nsp4 SP; chymotrypsin-like serine proteinase nsp4
Comments: In the equine arterivirus (EAV), the replicase gene is translated into open reading frame 1a (ORF1a) and ORF1ab polyproteins. This enzyme is the main viral proteinase and processes five cleavage sites in the ORF1a protein and three in the ORF1b-encoded part of the ORF1ab protein to yield nonstructural proteins (nsp5-nsp12) [3]. It combines the catalytic system of a chymotrypsin-like serine peptidase (His-Asp-Ser catalytic triad) with the substrate specificity of a 3C-like serine peptidase (Glu or Gln) at the P1 position and a small amino-acid residue (Gly, Ser or Ala) at the P1′ position [1]. Cleavage of ORF1ab by this enzyme is essential for viral replication [2]. Belongs in peptidase family S32.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc
References:
1.  Snijder, E.J., Wassenaar, A.L., van Dinten, L.C., Spaan, W.J. and Gorbalenya, A.E. The arterivirus nsp4 protease is the prototype of a novel group of chymotrypsin-like enzymes, the 3C-like serine proteases. J. Biol. Chem. 271 (1996) 4864–4871. [DOI] [PMID: 8617757]
2.  van Dinten, L.C., Rensen, S., Gorbalenya, A.E. and Snijder, E.J. Proteolytic processing of the open reading frame 1b-encoded part of arterivirus replicase is mediated by nsp4 serine protease and is essential for virus replication. J. Virol. 73 (1999) 2027–2037. [PMID: 9971783]
3.  Barrette-Ng, I.H., Ng, K.K., Mark, B.L., Van Aken, D., Cherney, M.M., Garen, C., Kolodenko, Y., Gorbalenya, A.E., Snijder, E.J. and James, M.N. Structure of arterivirus nsp4. The smallest chymotrypsin-like proteinase with an α/β C-terminal extension and alternate conformations of the oxyanion hole. J. Biol. Chem. 277 (2002) 39960–39966. [DOI] [PMID: 12163505]
[EC 3.4.21.114 created 2006]
 
 
EC 3.4.21.115     
Accepted name: infectious pancreatic necrosis birnavirus Vp4 peptidase
Reaction: Cleaves the (Ser/Thr)-Xaa-Ala┼(Ser/Ala)-Gly motif in the polyprotein NH2-pVP2-VP4-VP3-COOH of infectious pancreatic necrosis virus at the pVP2-VP4 and VP4-VP3 junctions
Other name(s): infectious pancreatic necrosis virus protease; IPNV Vp4 protease; IPNV Vp4 peptidase; NS protease; NS-associated protease; Vp4 protease
Comments: Infectious pancreatic necrosis virus (IPNV) is a birnavirus that causes an acute, contagious disease in young salmonid fish [2]. As with most viruses that infect eukaryotic cells, the proteolytic processing of viral precursor proteins is a crucial step in the life cycle of this virus [2]. pVP2 is converted into VP2 by cleavage near the carboxy end of pVP2. This cleavage is most likely due to host-cell proteases rather than VP4 [2,3]. Differs from most serine peptidases in not having the catalytic triad Ser-His-Asp [2]. Belongs in peptidase family S50.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc
References:
1.  Manning, D.S. and Leong, J.C. Expression in Escherichia coli of the large genomic segment of infectious pancreatic necrosis virus. Virology 179 (1990) 16–25. [PMID: 2219718]
2.  Petit, S., Lejal, N., Huet, J.C. and Delmas, B. Active residues and viral substrate cleavage sites of the protease of the birnavirus infectious pancreatic necrosis virus. J. Virol. 74 (2000) 2057–2066. [DOI] [PMID: 10666235]
3.  Dobos, P. The molecular biology of infectious pancreatic necrosis virus (IPNV). Annu. Rev. Fish Dis. 5 (1995) 25–54.
[EC 3.4.21.115 created 2006]
 
 
EC 3.4.21.116     
Accepted name: SpoIVB peptidase
Reaction: Self-cleaves Val52┼Asn53, Ala62┼Phe63 and Val74┼Thr75 at the N-terminus of SpoIVB
Other name(s): sporulation factor IV B protease
Comments: This enzyme plays a central role in a regulatory checkpoint (the σK checkpoint), which coordinates gene expression during the later stages of spore formation in Bacillus subtilis [1,3]. The enzyme activates proteolytic processing of a sporulation-specific sigma factor, pro-σK, to its mature and active form, σK, by self-cleavage [1,3]. The enzyme is also subject to secondary proteolysis, which presumably inactivates SpoIVB [3]. The enzyme is also essential for the formation of heat-resistant spores. Belongs in peptidase family S55.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, CAS registry number: 296241-18-4
References:
1.  Wakeley, P.R., Dorazi, R., Hoa, N.T., Bowyer, J.R. and Cutting, S.M. Proteolysis of SpolVB is a critical determinant in signalling of pro-σK processing in Bacillus subtilis. Mol. Microbiol. 36 (2000) 1336–1348. [DOI] [PMID: 10931284]
2.  Hoa, N.T., Brannigan, J.A. and Cutting, S.M. The PDZ domain of the SpoIVB serine peptidase facilitates multiple functions. J. Bacteriol. 183 (2001) 4364–4373. [DOI] [PMID: 11418578]
3.  Hoa, N.T., Brannigan, J.A. and Cutting, S.M. The Bacillus subtilis signaling protein SpoIVB defines a new family of serine peptidases. J. Bacteriol. 184 (2002) 191–199. [DOI] [PMID: 11741860]
4.  Dong, T.C. and Cutting, S.M. SpoIVB-mediated cleavage of SpoIVFA could provide the intercellular signal to activate processing of pro-σK in Bacillus subtilis. Mol. Microbiol. 49 (2003) 1425–1434. [DOI] [PMID: 12940997]
[EC 3.4.21.116 created 2006]
 
 
EC 3.4.21.118     
Accepted name: kallikrein 8
Reaction: Cleavage of amide substrates following the basic amino acids Arg or Lys at the P1 position, with a preference for Arg over Lys
Other name(s): KLK8; PRSS19; human kallikrein 8; hK8; mK8; ovasin; tumor-associated differentially expressed gene 14; TADG-14; NP; neuropsin
Comments: The enzyme is activated by removal of an N-terminal prepropeptide [2,4]. The highest amidolytic activity is observed using Boc-Val-Pro-Arg┼7-amido-4-methylcoumarin, which is a substrate of α-thrombin [2,4]. Substrates lacking basic amino acids in the P1 position are not cleaved [4]. The enzyme degrades casein, fibronectin, gelatin, collagen type IV, fibrinogen, and high-molecular-mass kininogen [3] and is associated with diseases such as ovarian cancer and Alzheimer’s disease [4]. Belongs in peptidase family S1A.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, PDB, CAS registry number: 171715-15-4
References:
1.  Chen, Z.L., Yoshida, S., Kato, K., Momota, Y., Suzuki, J., Tanaka, T., Ito, J., Nishino, H., Aimoto, S., Kiyama, H. and Shiosaka, S. Expression and activity-dependent changes of a novel limbic-serine protease gene in the hippocampus. J. Neurosci. 15 (1995) 5088–5097. [PMID: 7623137]
2.  Shimizu, C., Yoshida, S., Shibata, M., Kato, K., Momota, Y., Matsumoto, K., Shiosaka, T., Midorikawa, R., Kamachi, T., Kawabe, A. and Shiosaka, S. Characterization of recombinant and brain neuropsin, a plasticity-related serine protease. J. Biol. Chem. 273 (1998) 11189–11196. [DOI] [PMID: 9556608]
3.  Rajapakse, S., Ogiwara, K., Takano, N., Moriyama, A. and Takahashi, T. Biochemical characterization of human kallikrein 8 and its possible involvement in the degradation of extracellular matrix proteins. FEBS Lett. 579 (2005) 6879–6884. [DOI] [PMID: 16337200]
4.  Kishi, T., Cloutier, S.M., Kündig, C., Deperthes, D. and Diamandis, E.P. Activation and enzymatic characterization of recombinant human kallikrein 8. Biol. Chem. 387 (2006) 723–731. [DOI] [PMID: 16800733]
[EC 3.4.21.118 created 2006]
 
 
EC 3.4.21.120     
Accepted name: oviductin
Reaction: Preferential cleavage at Gly-Ser-Arg373┼ of glycoprotein gp43 in Xenopus laevis coelemic egg envelope to yield gp41
Other name(s): oviductal protease
Comments: The egg envelope of the South African clawed frog (Xenopus laevis) is modified during transit of the egg through the pars rectus oviduct, changing the egg envelope from an unfertilizable form to a fertilizable form. This process involves the conversion of glycoprotein gp43 to gp41 (ZPC) by the pars recta protease oviductin. It is thought that the enzymically active protease molecule comprises the N-terminal protease domain coupled to two C-terminal CUB domains, which are related to the mammalian spermadhesin molecules implicated in mediating sperm-envelope interactions [2]. The enzyme is also found in the Japanese toad (Bufo japonicus) [3]. Belongs in peptidase family S1.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc
References:
1.  Hardy, D.M. and Hedrick, J.L. Oviductin. Purification and properties of the oviductal protease that processes the molecular weight 43,000 glycoprotein of the Xenopus laevis egg envelope. Biochemistry 31 (1992) 4466–4472. [PMID: 1581303]
2.  Lindsay, L.L., Wieduwilt, M.J. and Hedrick, J.L. Oviductin, the Xenopus laevis oviductal protease that processes egg envelope glycoprotein gp43, increases sperm binding to envelopes, and is translated as part of an unusual mosaic protein composed of two protease and several CUB domains. Biol. Reprod. 60 (1999) 989–995. [PMID: 10084976]
3.  Hiyoshi, M., Takamune, K., Mita, K., Kubo, H., Sugimoto, Y. and Katagiri, C. Oviductin, the oviductal protease that mediates gamete interaction by affecting the vitelline coat in Bufo japonicus: its molecular cloning and analyses of expression and posttranslational activation. Dev. Biol. 243 (2002) 176–184. [DOI] [PMID: 11846486]
[EC 3.4.21.120 created 2007]
 
 
EC 3.4.21.121     
Accepted name: Lys-Lys/Arg-Xaa endopeptidase
Reaction: Cleavage of -Lys-Lys┼ and -Lys-Arg┼ bonds.
Other name(s): ASP (Aeromonas sobria)-type peptidase; Aeromonas extracellular serine protease
Comments: The enzyme is a serine peptidase, which has been shown to cleave prothrombin and prekallikrein. It hydrolyses the complement component C5 releasing complement component C5a.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc
References:
1.  Kobayashi, H., Utsunomiya, H., Yamanaka, H., Sei, Y., Katunuma, N., Okamoto, K. and Tsuge, H. Structural basis for the kexin-like serine protease from Aeromonas sobria as sepsis-causing factor. J. Biol. Chem. 284 (2009) 27655–27663. [DOI] [PMID: 19654332]
2.  Nitta, H., Kobayashi, H., Irie, A., Baba, H., Okamoto, K. and Imamura, T. Activation of prothrombin by ASP, a serine protease released from Aeromonas sobria. FEBS Lett. 581 (2007) 5935–5939. [DOI] [PMID: 18067862]
3.  Kobayashi, H., Takahashi, E., Oguma, K., Fujii, Y., Yamanaka, H., Negishi, T., Arimoto-Kobayashi, S., Tsuji, T. and Okamoto, K. Cleavage specificity of the serine protease of Aeromonas sobria, a member of the kexin family of subtilases. FEMS Microbiol. Lett. 256 (2006) 165–170. [DOI] [PMID: 16487335]
4.  Imamura, T., Nitta, H., Wada, Y., Kobayashi, H. and Okamoto, K. Impaired plasma clottability induction through fibrinogen degradation by ASP, a serine protease released from Aeromonas sobria. FEMS Microbiol. Lett. 284 (2008) 35–42. [DOI] [PMID: 18462393]
5.  Nitta, H., Imamura, T., Wada, Y., Irie, A., Kobayashi, H., Okamoto, K. and Baba, H. Production of C5a by ASP, a serine protease released from Aeromonas sobria. J. Immunol. 181 (2008) 3602–3608. [DOI] [PMID: 18714034]
[EC 3.4.21.121 created 2013]
 
 
EC 3.4.22.2     
Accepted name: papain
Reaction: Hydrolysis of proteins with broad specificity for peptide bonds, but preference for an amino acid bearing a large hydrophobic side chain at the P2 position. Does not accept Val in P1′
Other name(s): papayotin; summetrin; velardon; papaine; Papaya peptidase I
Comments: Type example of peptidase family C1 from latex of the papaya (Carica papaya) fruit. Inhibited by compound E-64 and proteins of the cystatin family.
Links to other databases: BRENDA, EXPASY, GTD, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 9001-73-4
References:
1.  Kamphuis, I.G., Drenth, J. and Baker, E.N. Thiol proteases. Comparative studies based on the high-resolution structures of papain and actinidin, and on amino acid sequence information for cathepsins B and H, and stem bromelain. J. Mol. Biol. 182 (1985) 317–329. [DOI] [PMID: 3889350]
2.  Ménard, R. and Storer, A.C. Papain. In: Barrett, A.J., Rawlings, N.D. and Woessner, J.F. (Eds), Handbook of Proteolytic Enzymes, Academic Press, London, 1998, pp. 555–557.
[EC 3.4.22.2 created 1961 as EC 3.4.4.10, transferred 1972 to EC 3.4.22.2, modified 1976, modified 2000]
 
 
EC 3.4.22.10     
Accepted name: streptopain
Reaction: Preferential cleavage with hydrophobic residues at P2, P1 and P1′
Other name(s): Streptococcus peptidase A; streptococcal cysteine proteinase; Streptococcus protease
Comments: From the bacterium, group A Streptococcus. Formed from the proenzyme by limited proteolysis. Type example of peptidase family C10.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 9025-51-8
References:
1.  Elliott, S.D. and Liu, T.-Y. Streptococcal proteinase. Methods Enzymol. 19 (1970) 252–261.
2.  Liu, T.-Y. and Elliott, S.D. Streptococcal proteinase. In: Boyer, P.D. (Ed.), The Enzymes, 3rd edn, Academic Press, New York, 1971, pp. 609–647.
3.  Tai, J. Y., Kortt, A.A., Liu, T.-Y. and Elliott, S.D. Primary structure of streptococcal proteinase. III. Isolation of cyanogen bromide peptides: complete covalent structure of the polypeptide chain. J. Biol. Chem. 251 (1976) 1955–1959. [PMID: 1270417]
4.  Lo, S.-S., Fraser, B.A. and Liu, T.-Y. The mixed disulphide in the zymogen of streptococcal proteinase. Characterization and implication for its biosynthesis. J. Biol. Chem. 259 (1984) 11041–11045. [PMID: 6381494]
[EC 3.4.22.10 created 1961 as EC 3.4.4.18, transferred 1972 to EC 3.4.22.10]
 
 
EC 3.4.22.14     
Accepted name: actinidain
Reaction: Similar to that of papain
Other name(s): actinidin; Actinidia anionic protease; proteinase A2 of Actinidia chinensis
Comments: From the kiwi fruit or Chinese gooseberry (Actinidia chinensis). In peptidase family C1 (papain family)
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 39279-27-1
References:
1.  Baker, E.N., Boland, M.J., Calder, P.C. and Hardman, M.J. The specificity of actinidin and its relationship to the structure of the enzyme. Biochim. Biophys. Acta 616 (1980) 30–34. [DOI] [PMID: 7002215]
2.  Kamphuis, I.G., Drenth, J. and Baker, E.N. Thiol proteases. Comparative studies based on the high-resolution structures of papain and actinidin, and on amino acid sequence information for cathepsins B and H, and stem bromelain. J. Mol. Biol. 182 (1985) 317–329. [DOI] [PMID: 3889350]
3.  Baker, E.N. and Drenth, J. The thiol proteases: stucture and mechanism. In: Jurnak, F.A. and McPherson, A. (Eds), Biological Macromolecules and Assemblies: Active Sites of Enzymes, vol. 3, John Wiley and Sons, New York, 1987, pp. 314–368.
[EC 3.4.22.14 created 1978]
 
 
EC 3.4.22.27     
Accepted name: cathepsin S
Reaction: Similar to cathepsin L, but with much less activity on Z-Phe-Arg┼NHMec, and more activity on the Z-Val-Val-Arg┼ compound
Comments: A lysosomal cysteine endopeptidase that is unusual amongst such enzymes for its stability to neutral pH. In peptidase family C1 (papain family)
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 71965-46-3
References:
1.  Turnšek, T., Kregar, I. and Lebez, D. Acid sulphydryl protease from calf lymph nodes. Biochim. Biophys. Acta 403 (1975) 514–520. [DOI] [PMID: 1182153]
2.  Brömme, D., Steinert, A., Friebe, S., Fittkau, S., Wiederanders, B. and Kirschke, H. The specificity of bovine spleen cathepsin S. A comparison with rat liver cathepsins L and B. Biochem. J. 264 (1989) 475–485. [PMID: 2604727]
3.  Kirschke, H., Wiederanders, B., Brömme, D. and Rinne, A. Cathepsin S from bovine spleen. Purification, distribution, intracellular localization and action on proteins. Biochem. J. 264 (1989) 467–473. [PMID: 2690828]
[EC 3.4.22.27 created 1992]
 
 
EC 3.4.22.28     
Accepted name: picornain 3C
Reaction: Selective cleavage of Gln┼Gly bond in the poliovirus polyprotein. In other picornavirus reactions Glu may be substituted for Gln, and Ser or Thr for Gly
Other name(s): picornavirus endopeptidase 3C; poliovirus protease 3C; rhinovirus protease 3C; foot-and-mouth protease 3C; poliovirus proteinase 3C; rhinovirus proteinase 3C; coxsackievirus 3C proteinase; foot-and-mouth-disease virus proteinase 3C; 3C protease; 3C proteinase; cysteine proteinase 3C; hepatitis A virus 3C proteinase; protease 3C; tomato ringspot nepovirus 3C-related protease
Comments: From entero-, rhino-, aphto- and cardioviruses. Larger than the homologous virus picornain 2A. Type example of peptidase family C3
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 97162-88-4
References:
1.  Ivanoff, L.A., Towatari, T., Ray, J., Korant, B.D. and Petteway, S.R. Expression and site-specific mutagenesis of the poliovirus 3C protease in Escherichia coli. Proc. Natl Acad. Sci. USA 83 (1986) 5392–5396. [DOI] [PMID: 3016701]
2.  Bazan, J.F. and Fletterick, R.J. Viral cysteine proteases are homologous to the trypsin-like family of serine proteases: structural and functional implications. Proc. Natl Acad. Sci. USA 85 (1988) 7872–7876. [DOI] [PMID: 3186696]
3.  Kräusslich, H.-G. and Wimmer, E. Viral proteinases. Annu. Rev. Biochem. 57 (1988) 701–754. [DOI] [PMID: 3052288]
4.  Nicklin, M.J.H., Harris, K.S., Pallai, P.V. and Wimmer, E. Poliovirus proteinase 3C: large-scale expression, purification, and specific cleavage activity on natural and synthetic substrates in vitro. J. Virol. 62 (1988) 4586–4593. [PMID: 2846872]
[EC 3.4.22.28 created 1992]
 
 
EC 3.4.22.29     
Accepted name: picornain 2A
Reaction: Selective cleavage of Tyr┼Gly bond in picornavirus polyprotein
Other name(s): picornavirus endopeptidase 2A; poliovirus protease 2A; rhinovirus protease 2A; 2A protease; 2A proteinase; protease 2A; proteinase 2Apro; picornaviral 2A proteinase; Y-G proteinase 2A; poliovirus proteinase 2A; poliovirus protease 2Apro; picornaviral 2A proteinase
Comments: From entero-, rhino-, aphto- and cardioviruses. Smaller than the homologous picornain 3C, which is also in peptidase family C3 (picornain 3C family)
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 103406-62-8
References:
1.  Bazan, J.F. and Fletterick, R.J. Viral cysteine proteases are homologous to the trypsin-like family of serine proteases: structural and functional implications. Proc. Natl Acad. Sci. USA 85 (1988) 7872–7876. [DOI] [PMID: 3186696]
2.  König, H. and Rosenwirth, B. Purification and partial characterization of poliovirus protease 2A by means of a functional assay. J. Virol. 62 (1988) 1243–1250. [PMID: 2831385]
3.  Kräusslich, H.-G. and Wimmer, E. Viral proteinases. Annu. Rev. Biochem. 57 (1988) 701–754. [DOI] [PMID: 3052288]
[EC 3.4.22.29 created 1992]
 
 
EC 3.4.22.33     
Accepted name: fruit bromelain
Reaction: Hydrolysis of proteins with broad specificity for peptide bonds. Bz-Phe-Val-Arg┼NHMec is a good synthetic substrate, but there is no action on Z-Arg-Arg-NHMec (c.f. stem bromelain)
Other name(s): juice bromelain; ananase; bromelase; bromelin; extranase; juice bromelain; pinase; pineapple enzyme; traumanase; fruit bromelain FA2
Comments: From the pineapple plant, Ananas comosus. Scarcely inhibited by chicken cystatin. Another cysteine endopeptidase, with similar action on small molecule substrates, pinguinain, is obtained from the related plant, Bromelia pinguin, but pinguinain differs from fruit bromelain in being inhibited by chicken cystatin [4].
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, CAS registry number: 9001-00-7
References:
1.  Sasaki, M., Kato, T. and Iida, S. Antigenic determinant common to four kinds of thiol proteases of plant origin. J. Biochem. (Tokyo) 74 (1973) 635–637. [PMID: 4127920]
2.  Yamada, F., Takahashi, N. and Murachi, T. Purification and characterization of a proteinase from pineapple fruit, fruit bromelain FA2. J. Biochem. (Tokyo) 79 (1976) 1223–1234. [PMID: 956152]
3.  Ota, S., Muta, E., Katanita, Y. and Okamoto, Y. Reinvestigation of fractionation and some properties of the proteolytically active components of stem and fruit bromelains. J. Biochem. (Tokyo) 98 (1985) 219–228. [PMID: 4044551]
4.  Rowan, A.D., Buttle, D.J. and Barrett, A.J. The cysteine proteinases of the pineapple plant. Biochem. J. 266 (1990) 869–875. [PMID: 2327970]
[EC 3.4.22.33 created 1965 as EC 3.4.4.24, transferred 1972 to EC 3.4.22.4, part transferred 1992 to EC 3.4.22.33]
 
 
EC 3.4.22.35     
Accepted name: histolysain
Reaction: Hydrolysis of proteins, including basement membrane collagen and azocasein. Preferential cleavage: Arg-Arg┼ in small molecule substrates including Z-Arg-Arg┼NHMec
Other name(s): histolysin; histolysin; Entamoeba histolytica cysteine proteinase; amebapain; Entamoeba histolytica cysteine protease; Entamoeba histolytica neutral thiol proteinase
Comments: From the protozoan, Entamoeba histolytica. In peptidase family C1 (papain family)
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, CAS registry number: 92228-52-9
References:
1.  Lushbaugh, W.B., Hofbauer, A.F. and Pittman, F.E. Entamoeba histolytica: purification of cathepsin B. Exp. Parasitol. 59 (1985) 328–336. [PMID: 2860002]
2.  Luaces, A.L. and Barrett, A.J. Affinity purification and biochemical characterization of histolysin: the major cysteine proteinase of Entamoeba histolytica. Biochem. J. 250 (1988) 903–909. [PMID: 2898937]
[EC 3.4.22.35 created 1992]
 
 
EC 3.4.22.36     
Accepted name: caspase-1
Reaction: Strict requirement for an Asp residue at position P1 and has a preferred cleavage sequence of Tyr-Val-Ala-Asp┼
Other name(s): interleukin 1β-converting enzyme; protease VII; protease A; interleukin 1β precursor proteinase; interleukin 1 converting enzyme; interleukin 1β-converting endopeptidase; interleukin-1β convertase; interleukin-1β converting enzyme; interleukin-1β precursor proteinase; prointerleukin 1β protease; precursor interleukin-1β converting enzyme; pro-interleukin 1β proteinase; ICE
Comments: From mammalian monocytes. This enzyme is part of the family of inflammatory caspases, which also includes caspase-4 (EC 3.4.22.57) and caspase-5 (EC 3.4.22.58) in humans and caspase-11 (EC 3.4.22.64), caspase-12, caspase-13 and caspase-14 in mice. Contains a caspase-recruitment domain (CARD) in its N-terminal prodomain, which plays a role in procaspase activation [6,7]. Cleaves pro-interleukin-1β (pro-IL-1β) to form mature IL-1β, a potent mediator of inflammation. Also activates the proinflammatory cytokine, IL-18, which is also known as interferon-γ-inducing factor [6]. Inhibited by Ac-Tyr-Val-Ala-Asp-CHO. Caspase-11 plays a critical role in the activation of caspase-1 in mice, whereas caspase-4 enhances its activation in humans [7]. Belongs in peptidase family C14.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 122191-40-6
References:
1.  Howard, A., Kostura, M.J., Thornberry, N., Ding, G.J.., Limjuco, G., Weidner, J., Salley, J.P., Hogquist, K.A., Chaplin, D.D., Mumford, R.A., Schmidt, J.A. and Tocci, M.J. IL-1 converting enzyme requires aspartic acid residues for processing of the IL-1β precursor at two distinct sites and does not cleave 31-kDa IL-1α. J. Immunol. 147 (1991) 2964–2969. [PMID: 1919001]
2.  Thornberry, N.A., Bull, H.G., Calaycay, J.R., Chapman, K.T., Howard, A.D., Kostura, M.J., Miller, D.K., Molineaux, S.M., Weidner, J.R., Aunins, J., Elliston, K.O., Ayala, J.M., Casano, F J., Chin, J., Ding, G.J.-F., Egger, L.A., Gaffney, E.P., Limjuco, G., Palyha, O.C., Raju, S.M., Rolando, A.M., Salley, J.P., Yamin, T.-T. and Tocci, M.J. A novel heterodimeric cysteine protease is required for interleukin-1β processing in monocytes. Nature 356 (1992) 768–774. [DOI] [PMID: 1574116]
3.  Thornberry, N.A. Interleukin-1β converting enzyme. Methods Enzymol. 244 (1994) 615–631. [PMID: 7845238]
4.  Alnemri, E.S., Livingston, D.J., Nicholson, D.W., Salvesen, G., Thornberry, N.A., Wong, W.W. and Yuan, J.Y. Human ICE/CED-3 protease nomenclature. Cell 87 (1996) 171. [DOI] [PMID: 8861900]
5.  Margolin, N., Raybuck, S.A., Wilson, K.P., Chen, W.Y., Fox, T., Gu, Y. and Livingston, D.J. Substrate and inhibitor specificity of interleukin-1β-converting enzyme and related caspases. J. Biol. Chem. 272 (1997) 7223–7228. [DOI] [PMID: 9054418]
6.  Martinon, F. and Tschopp, J. Inflammatory caspases: linking an intracellular innate immune system to autoinflammatory diseases. Cell 117 (2004) 561–574. [DOI] [PMID: 15163405]
7.  Chang, H.Y. and Yang, X. Proteases for cell suicide: functions and regulation of caspases. Microbiol. Mol. Biol. Rev. 64 (2000) 821–846. [PMID: 11104820]
[EC 3.4.22.36 created 1993, modified 1997, modified 2007]
 
 
EC 3.4.22.37     
Accepted name: gingipain R
Reaction: Hydrolysis of proteins and small molecule substrates, with a preference for Arg in P1
Other name(s): Arg-gingipain; gingipain-1; argingipain; Arg-gingivain-55 proteinase; Arg-gingivain-70 proteinase; Arg-gingivain-75 proteinase; arginine-specific cysteine protease; arginine-specific gingipain; arginine-specific gingivain; RGP-1; RGP
Comments: A secreted endopeptidase from the bacterium Porphyromonas gingivalis. Strongly activated by glycine [1], and stabilized by Ca2+. Precursor molecule contains a hemagglutinin domain [2,3]. Misleadingly described in some literature as "trypsin-like", being a cysteine peptidase, type example of family C25
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 159745-71-8
References:
1.  Chen, Z., Potempa, J., Polanowski, A., Wikstrom, M. and Travis, J. Purification and characterization of a 50-kDa cysteine proteinase (gingipain) from Porphyromonas gingivalis. J. Biol. Chem. 267 (1992) 18896–18901. [PMID: 1527017]
2.  Kirszbaum, L., Sotiropoulos, C., Jackson, C., Cleal, S., Slakeski, N. and Reynolds, E.C. Complete nucleotide sequence of a gene prtR of Porphyromonas gingivalis W50 encoding a 132 kDa protein that contains an arginine-specific thiol endopeptidase domain and a haemagglutinin domain. Biochem. Biophys. Res. Commun. 207 (1995) 424–431. [DOI] [PMID: 7857299]
3.  Pavloff, N., Potempa, J., Pike, R.N., Prochazka, V., Kiefer, M.C., Travis, J. and Barr, P.J. Molecular cloning and structural characterization of the Arg-gingipain proteinase of Porphyromonas gingivalis. Biosynthesis as a proteinase-adhesin polyprotein. J. Biol. Chem. 270 (1995) 1007–1010. [DOI] [PMID: 7836351]
[EC 3.4.22.37 created 1996]
 
 
EC 3.4.22.38     
Accepted name: cathepsin K
Reaction: Broad proteolytic activity. With small-molecule substrates and inhibitors, the major determinant of specificity is P2, which is preferably Leu, Met > Phe, and not Arg
Other name(s): cathepsin O and cathepsin X (both misleading, having been used for other enzymes); cathepsin O2
Comments: Prominently expressed in mammalian osteoclasts, and believed to play a role in bone resorption. In peptidase family C1 (papain family)
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 94716-09-3
References:
1.  Inaoka, T., Bilbe, G., Ishibashi, O., Tezuka, K., Kumegawa, M. and Kokubo, T. Molecular cloning of human cDNA for cathepsin K: Novel cysteine proteinase predominantly expressed in bone. Biochem. Biophys. Res. Commun. 206 (1995) 89–96. [DOI] [PMID: 7818555]
2.  Bossard, M.J., Tomaszek, T.A., Thompson, S.K., Amegadzie, B.Y., Hanning, C.R., Jones, C., Kurdyla, J.T., McNulty, D.E., Drake, F.H., Gowen, M. and Levy, M.A. Proteolytic activity of human osteoclast cathepsin K - Expression, purification, activation, and substrate identification. J. Biol. Chem. 271 (1996) 12517–12524. [DOI] [PMID: 8647860]
3.  Bromme, D., Klaus, J.L., Okamoto, K., Rasnick, D. and Palmer, J.T. Peptidyl vinyl sulphones: A new class of potent and selective cysteine protease inhibitors - S2P2 specificity of human cathepsin O2 in comparison with cathepsins S and L. Biochem. J. 315 (1996) 85–89. [PMID: 8670136]
4.  Zhao, B.G., Janson, C.A., Amegadzie, B.Y., D'Alessio, K., Griffin, C., Hanning, C.R., Jones, C., Kurdyla, J., McQueney, M., Qiu, X.Y., Smith, W.W. and Abdel-Meguid, S.S. Crystal structure of human osteoclast cathepsin K complex with E-64. Nature Struct. Biol. 4 (1997) 109–111. [PMID: 9033588]
5.  McGrath, M.E., Klaus, J.L., Barnes, M.G. and Brömme, D. Crystal structure of human cathepsin K complexed with a potent inhibitor. Nature Struct. Biol. 4 (1997) 105–109. [PMID: 9033587]
[EC 3.4.22.38 created 1997]
 
 
EC 3.4.22.39     
Accepted name: adenain
Reaction: Cleaves proteins of the adenovirus and its host cell at two consensus sites: -Yaa-Xaa-Gly-Gly┼Xaa- and -Yaa-Xaa-Gly-Xaa┼Gly- (in which Yaa is Met, Ile or Leu, and Xaa is any amino acid)
Comments: A cysteine endopeptidase from adenoviruses, the type example of peptidase family C5, with a protein fold unlike that known for any other peptidase [2]. Activity is greatly stimulated by the binding to the enzyme of an 11-residue peptide from the adenovirus capsid protein pre-VI at a site separate from the active site [1]
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 369652-03-9
References:
1.  Webster, A., Hay, R.T. and Kemp, G. The adenovirus protease is activated by a virus-coded disulphide-linked peptide. Cell 72 (1993) 274–275. [DOI] [PMID: 8422686]
2.  Ding, J.Z., McGrath, W.J., Sweet, R.M. and Mangel, W.F. Crystal structure of the human adenovirus proteinase with its 11 residue cofactor. EMBO J. 15 (1996) 1778–1783. [PMID: 8617222]
3.  Weber, J.M. Adenovirus protease. In: Barrett, A.J., Rawlings, N.D. and Woessner, J.F. (Eds), Handbook of Proteolytic Enzymes, Academic Press, London, 1998, pp. 741–743.
[EC 3.4.22.39 created 2000]
 
 
EC 3.4.22.41     
Accepted name: cathepsin F
Reaction: The recombinant enzyme cleaves synthetic substrates with Phe and Leu (better than Val) in P2, with high specificity constant (kcat/Km) comparable to that of cathepsin L
Comments: Cathepsin F is a lysosomal cysteine endopeptidase of family C1 (papain family), most active at pH 5.9. The enzyme is unstable at neutral pH values and is inhibited by compound E-64. Cathepsin F is expressed in most tissues of human, mouse and rat. Human gene locus: 11q13.1-13.3
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 65997-74-2
References:
1.  Santamaría, I., Velasco, G., Pendás, A.M., Paz, A. and López-Otín, C. Molecular cloning and structural and functional chararcterization of cathepsin F, a new cysteine proteinase of the papain family with a long propeptide domain. J. Biol. Chem. 274 (1999) 13800–13809. [DOI] [PMID: 10318784]
2.  Nägler, D.K. Sulea, T. and Ménard, R. Full length cDNA of human cathepsin F predicts the presence of a cystatin domain at the N-terminus of the cysteine protease zymogen. Biochem. Biophys. Res. Commun. 257 (1999) 313–318. [DOI] [PMID: 10198209]
3.  Wex, T., Levy, B., Wex, H. and Brömme, D. Human cathepsins F and W: A new subgroup of cathepsins. Biochem. Biophys. Res. Commun. 259 (1999) 401–407. [DOI] [PMID: 10362521]
4.  Wang, B., Shi, G.-P., Yao, P.M., Li, Z., Chapman, H.A. and Brömme, D. Human cathepsin F. Molecular cloning, functional expression, tissue localization, and enzymatic characterization. J. Biol. Chem. 273 (1998) 32000–32008. [DOI] [PMID: 9822672]
[EC 3.4.22.41 created 2000]
 
 
EC 3.4.22.44     
Accepted name: nuclear-inclusion-a endopeptidase
Reaction: Hydrolyses glutaminyl bonds, and activity is further restricted by preferences for the amino acids in P6 - P1′ that vary with the species of potyvirus, e.g. Glu-Xaa-Xaa-Tyr-Xaa-Gln┼(Ser or Gly) for the enzyme from tobacco etch virus. The natural substrate is the viral polyprotein, but other proteins and oligopeptides containing the appropriate consensus sequence are also cleaved.
Other name(s): potyvirus NIa protease
Comments: The potyviruses cause diseases in plants, and inclusion bodies appear in the host cell nuclei; protein a of the inclusion bodies is the endopeptidase. The enzyme finds practical use when encoded in vectors for the artificial expression of recombinant fusion proteins, since it can confer on them the capacity for autolytic cleavage. It is also reported that transgenic plants expressing the enzyme are resistant to viral infection. Type example of peptidase family C4.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 139946-51-3
References:
1.  Fellers, J.P., Collins, G.B. and Hunt, A.G. The NIa-proteinase of different plant potyviruses provides specific resistance to viral infection. Crop Sci. 38 (1998) 1309–1319.
2.  Kim, D.-H. and Choi, K.Y. Potyvirus NIa protease. In: Barrett, A.J., Rawlings, N.D. and Woessner, J.F. (Eds), Handbook of Proteolytic Enzymes, Academic Press, London, 1998, pp. 721–723.
3.  Takahashi, T., Nakanishi, M., Yao, Y., Uyeda, I. and Serizawa, N. Direct formation of human interleukin-11 by cis-acting system of plant virus protease in Escherichia coli. Biosci. Biotechnol. Biochem. 62 (1998) 953–958. [PMID: 9648226]
4.  Kim, D.H., Hwang, D.C., Kang, B.H., Lew, J., Han, J.S., Song, B.O.D. and Choi, K.Y. Effects of internal cleavages and mutations in the C-terminal region of NIa protease of turnip mosaic potyvirus on the catalytic activity. Virology 226 (1996) 183–190. [DOI] [PMID: 8955037]
[EC 3.4.22.44 created 2000]
 
 
EC 3.4.22.47     
Accepted name: gingipain K
Reaction: Endopeptidase with strict specificity for lysyl bonds
Other name(s): Lys-gingipain; PrtP proteinase
Comments: Activity is stimulated by glycine. Known from the bacterium Porphyromonas gingivalis and contributes to the pathogenicity of the organism. In peptidase family C25.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, SWISSPROT, CAS registry number: 159745-69-4
References:
1.  Pike, R., McGraw, W., Potempa, J. and Travis, J. Lysine- and arginine-specific proteinases from Porphyromonas gingivalis. Isolation, characterization, and evidence for the existence of complexes with hemagglutinins. J. Biol. Chem. 269 (1994) 406–411. [PMID: 8276827]
2.  Curtis, M.A., Aduse, O.J., Rangarajan, M., Gallagher, A., Sterne, J.A., Reid, C.R., Evans, H.E. and Samuelsson, B. Attenuation of the virulence of Porphyromonas gingivalis by using a specific synthetic Kgp protease inhibitor 2. Infect. Immun. 70 (2002) 6968–6975. [DOI] [PMID: 12438376]
[EC 3.4.22.47 created 2003]
 
 
EC 3.4.22.48     
Accepted name: staphopain
Reaction: Broad endopeptidase action on proteins including elastin, but rather limited hydrolysis of small-molecule substrates. Assays are conveniently made with hemoglobin, casein or Z-Phe-Arg-NHMec as substrate
Other name(s): staphylopain
Comments: Known from species of Staphylococcus. Type example of peptidase family C47.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, SWISSPROT, CAS registry number: 347841-89-8
References:
1.  Hofmann, B., Hecht, H.J., Kiess, M. and Schomburg, D. Crystal structure of a thiol proteinase from Staphylococcus aureus V8 in the E-64 inhibitor complex. Acta Crystallogr. Sect. A (Suppl.) 49 (1993) 102.
2.  Potempa, J., Dubin, A. and Travis, J. Staphylopain. In: Barrett, A.J., Rawlings, N.D. and Woessner, J.F. (Eds), Handbook of Proteolytic Enzymes, Handbook of Proteolytic Enzymes, London, 1998, pp. 669–671.
3.  Dubin, G., Chmiel, D., Mak, P., Rakwalska, M., Rzychon, M. and Dubin, A. Molecular cloning and biochemical characterisation of proteases from Staphylococcus epidermidis. Biol. Chem. 382 (2001) 1575–1582. [DOI] [PMID: 11767947]
[EC 3.4.22.48 created 2003]
 
 
EC 3.4.22.50     
Accepted name: V-cath endopeptidase
Reaction: Endopeptidase of broad specificity, hydrolyzing substrates of both cathepsin L and cathepsin B
Other name(s): AcNPV protease; BmNPV protease; NPV protease; baculovirus cathepsin; nucleopolyhedrosis virus protease; viral cathepsin
Comments: In peptidase family C1. Contributes to the liquefaction of the tissues of the insect host in the late stages of infection by the baculovirus.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, SWISSPROT, CAS registry number: 316365-69-2
References:
1.  Slack, J.M., Kuzio, J. and Faulkner, P. Characterization of V-cath, a cathepsin L-like proteinase expressed by the baculovirus Autographa californica multiple nuclear polyhedrosis-virus. J. Gen. Virol. 76 (1995) 1091–1098. [DOI] [PMID: 7730794]
2.  Hawtin, R.E., Zarkowska, T., Arnold, K., Thomas, C.J., Gooday, G.W., King, L.A., Kuzio, J.A. and Possee, R.D. Liquefaction of Autographa californica nucleopolyhedrovirus-infected insects is dependent on the integrity of virus-encoded chitinase and cathepsin genes. Virology 238 (1997) 243–253. [DOI] [PMID: 9400597]
[EC 3.4.22.50 created 2003]
 
 
EC 3.4.22.52     
Accepted name: calpain-1
Reaction: Broad endopeptidase specificity
Other name(s): μ-calpain; calcium-activated neutral protease I
Comments: In peptidase family C2. Requires Ca2+ at micromolar concentrations for activity. Cytosolic in animal cells. The active enzyme molecule is a heterodimer in which the large subunit contains the peptidase unit, and the small subunit is also a component of EC 3.4.22.53, calpain-2.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, SWISSPROT, SWISSPROT, CAS registry number: 78990-62-2
References:
1.  Dutt, P., Spriggs, C.N., Davies, P.L., Jia, Z. and Elce, J.S. Origins of the difference in Ca2+ requirement for activation of μ- and m-calpain. Biochem. J. 367 (2002) 263–269. [DOI] [PMID: 12014988]
[EC 3.4.22.52 created 1981 as EC 3.4.22.17, transferred 2003 to EC 3.4.22.52]
 
 
EC 3.4.22.53     
Accepted name: calpain-2
Reaction: Broad endopeptidase specificity
Other name(s): calcium-activated neutral protease II; m-calpain; milli-calpain
Comments: Type example of peptidase family C2. Requires Ca2+ at millimolar concentrations for activity. Cytosolic in animal cells. The active enzyme molecule is a heterodimer in which the large subunit contains the peptidase unit, and the small subunit is also a component of EC 3.4.22.52, calpain-1.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, SWISSPROT, SWISSPROT, CAS registry number: 702693-80-9
References:
1.  Strobl, S., Fernandez-Catalan, C., Braun, M., Huber, R., Masumoto, H., Nakagawa, K., Irie, A., Sorimachi, H., Bourenkow, G., Bartunik, H., Suzuki, K. and Bode, W. The crystal structure of calcium-free human m-calpain suggests an electrostatic switch mechanism for activation by calcium. Proc. Natl. Acad. Sci. USA 97 (2000) 588–592. [DOI] [PMID: 10639123]
2.  Dutt, P., Spriggs, C.N., Davies, P.L., Jia, Z. and Elce, J.S. Origins of the difference in Ca2+ requirement for activation of μ- and m-calpain. Biochem. J. 367 (2002) 263–269. [DOI] [PMID: 12014988]
[EC 3.4.22.53 created 1981 as EC 3.4.22.17, transferred 2003 to EC 3.4.22.53]
 
 
EC 3.4.22.54     
Accepted name: calpain-3
Reaction: Broad endopeptidase activity
Other name(s): p94; calpain p94; CAPN3; muscle calpain; calpain 3; calcium-activated neutral proteinase 3; muscle-specific calcium-activated neutral protease 3; CANP 3; calpain L3
Comments: This Ca2+-dependent enzyme is found in skeletal muscle and is genetically linked to limb girdle muscular dystrophy type 2A [1,4]. The enzyme is activated by autoproteolytic cleavage of insertion sequence 1 (IS1), which allows substrates and inhibitors gain access to the active site [4]. Substrates include the protein itself [3,4] and connectin/titin [2,5]. Belongs in peptidase family C2.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc
References:
1.  Sorimachi, H., Imajoh-Ohmi, S., Emori, Y., Kawasaki, H., Ohno, S., Minami, Y. and Suzuki, K. Molecular cloning of a novel mammalian calcium-dependent protease distinct from both m- and μ-types. Specific expression of the mRNA in skeletal muscle. J. Biol. Chem. 264 (1989) 20106–20111. [PMID: 2555341]
2.  Sorimachi, H., Kinbara, K., Kimura, S., Takahashi, M., Ishiura, S., Sasagawa, N., Sorimachi, N., Shimada, H., Tagawa, K., Maruyama, K. and Suzuki, K. Muscle-specific calpain, p94, responsible for limb girdle muscular dystrophy type 2A, associates with connectin through IS2, a p94-specific sequence. J. Biol. Chem. 270 (1995) 31158–31162. [DOI] [PMID: 8537379]
3.  Rey, M.A. and Davies, P.L. The protease core of the muscle-specific calpain, p94, undergoes Ca2+-dependent intramolecular autolysis. FEBS Lett. 532 (2002) 401–406. [DOI] [PMID: 12482600]
4.  García Díaz, B.E., Gauthier, S. and Davies, P.L. Ca2+ dependency of calpain 3 (p94) activation. Biochemistry 45 (2006) 3714–3722. [DOI] [PMID: 16533054]
5.  Ono, Y., Torii, F., Ojima, K., Doi, N., Yoshioka, K., Kawabata, Y., Labeit, D., Labeit, S., Suzuki, K., Abe, K., Maeda, T. and Sorimachi, H. Suppressed disassembly of autolyzing p94/CAPN3 by N2A connectin/titin in a genetic reporter system. J. Biol. Chem. 281 (2006) 18519–18531. [DOI] [PMID: 16627476]
[EC 3.4.22.54 created 2007]
 
 
EC 3.4.22.55     
Accepted name: caspase-2
Reaction: Strict requirement for an Asp residue at P1, with Asp316 being essential for proteolytic activity and has a preferred cleavage sequence of Val-Asp-Val-Ala-Asp┼
Other name(s): ICH-1; NEDD-2; caspase-2L; caspase-2S; neural precursor cell expressed developmentally down-regulated protein 2; CASP-2; NEDD2 protein
Comments: Caspase-2 is an initiator caspase, as are caspase-8 (EC 3.4.22.61), caspase-9 (EC 3.4.22.62) and caspase-10 (EC 3.4.22.63) [6]. Contains a caspase-recruitment domain (CARD) in its N-terminal prodomain, which plays a role in procaspase activation [6]. Two forms of caspase-2 with antagonistic effects exist: caspase-2L induces programmed cell death and caspase-2S suppresses cell death [2,3,5]. Caspase-2 is activated by caspase-3 (EC 3.4.22.56), or by a caspase-3-like protease. Activation involves cleavage of the N-terminal prodomain, followed by self-proteolysis between the large and small subunits of pro-caspase-2 and further proteolysis into smaller fragments [3]. Proteolysis occurs at Asp residues and the preferred substrate for this enzyme is a pentapeptide rather than a tetrapeptide [5]. Apart from itself, the enzyme can cleave golgin-16, which is present in the Golgi complex and has a cleavage site that is unique for caspase-2 [4,5]. αII-Spectrin, a component of the membrane cytoskeleton, is a substrate of the large isoform of pro-caspase-2 (caspase-2L) but not of the short isoform (caspase-2S). Belongs in peptidase family C14.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, CAS registry number: 182372-14-1
References:
1.  Kumar, S., Kinoshita, M., Noda, M., Copeland, N.G. and Jenkins, N.A. Induction of apoptosis by the mouse Nedd2 gene, which encodes a protein similar to the product of the Caenorhabditis elegans cell death gene ced-3 and the mammalian IL-1β-converting enzyme. Genes Dev. 8 (1994) 1613–1626. [DOI] [PMID: 7958843]
2.  Wang, L., Miura, M., Bergeron, L., Zhu, H. and Yuan, J. Ich-1, an Ice/ced-3-related gene, encodes both positive and negative regulators of programmed cell death. Cell 78 (1994) 739–750. [DOI] [PMID: 8087842]
3.  Li, H., Bergeron, L., Cryns, V., Pasternack, M.S., Zhu, H., Shi, L., Greenberg, A. and Yuan, J. Activation of caspase-2 in apoptosis. J. Biol. Chem. 272 (1997) 21010–21017. [DOI] [PMID: 9261102]
4.  Mancini, M., Machamer, C.E., Roy, S., Nicholson, D.W., Thornberry, N.A., Casciola-Rosen, L.A. and Rosen, A. Caspase-2 is localized at the Golgi complex and cleaves golgin-160 during apoptosis. J. Cell Biol. 149 (2000) 603–612. [PMID: 10791974]
5.  Zhivotovsky, B. and Orrenius, S. Caspase-2 function in response to DNA damage. Biochem. Biophys. Res. Commun. 331 (2005) 859–867. [DOI] [PMID: 15865942]
6.  Chang, H.Y. and Yang, X. Proteases for cell suicide: functions and regulation of caspases. Microbiol. Mol. Biol. Rev. 64 (2000) 821–846. [PMID: 11104820]
[EC 3.4.22.55 created 2007]
 
 
EC 3.4.22.56     
Accepted name: caspase-3
Reaction: Strict requirement for an Asp residue at positions P1 and P4. It has a preferred cleavage sequence of Asp-Xaa-Xaa-Asp┼ with a hydrophobic amino-acid residue at P2 and a hydrophilic amino-acid residue at P3, although Val or Ala are also accepted at this position
Other name(s): CPP32; apopain; yama protein
Comments: Caspase-3 is an effector/executioner caspase, as are caspase-6 (EC 3.4.22.59) and caspase-7 (EC 3.4.22.60) [5]. These caspases are responsible for the proteolysis of the majority of cellular polypeptides [e.g. poly(ADP-ribose) polymerase (PARP)], which leads to the apoptotic phenotype [3,5]. Procaspase-3 can be activated by caspase-1 (EC 3.4.22.36), caspase-8 (EC 3.4.22.61), caspase-9 (EC 3.4.22.62) and caspase-10 (EC 3.4.22.63) as well as by the serine protease granzyme B [1]. Caspase-3 can activate procaspase-2 (EC 3.4.22.55) [2]. Activation occurs by inter-domain cleavage followed by removal of the N-terminal prodomain [6]. Although Asp-Glu-(Val/Ile)-Asp is thought to be the preferred cleavage sequence, the enzyme can accommodate different residues at P2 and P3 of the substrate [4]. Like caspase-2, a hydrophobic residue at P5 of caspase-3 leads to more efficient hydrolysis, e.g. (Val/Leu)-Asp-Val-Ala-Asp┼ is a better substrate than Asp-Val-Ala-Asp┼ . This is not the case for caspase-7 [4]. Belongs in peptidase family C14.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, PDB, CAS registry number: 169592-56-7
References:
1.  Krebs, J.F., Srinivasan, A., Wong, A.M., Tomaselli, K.J., Fritz, L.C. and Wu, J.C. Heavy membrane-associated caspase 3: identification, isolation, and characterization. Biochemistry 39 (2000) 16056–16063. [DOI] [PMID: 11123933]
2.  Li, H., Bergeron, L., Cryns, V., Pasternack, M.S., Zhu, H., Shi, L., Greenberg, A. and Yuan, J. Activation of caspase-2 in apoptosis. J. Biol. Chem. 272 (1997) 21010–21017. [DOI] [PMID: 9261102]
3.  Nicholson, D. and Thornberry, N.A. Caspase-3 and caspase-7. In: Barrett, A.J., Rawlings, N.D. and Woessner, J.F. (Eds), Handbook of Proteolytic Enzymes, 2nd edn, Elsevier, London, 2004, pp. 1298–1302.
4.  Fang, B., Boross, P.I., Tozser, J. and Weber, I.T. Structural and kinetic analysis of caspase-3 reveals role for S5 binding site in substrate recognition. J. Mol. Biol. 360 (2006) 654–666. [DOI] [PMID: 16781734]
5.  Chang, H.Y. and Yang, X. Proteases for cell suicide: functions and regulation of caspases. Microbiol. Mol. Biol. Rev. 64 (2000) 821–846. [PMID: 11104820]
6.  Martin, S.J., Amarante-Mendes, G.P., Shi, L., Chuang, T.H., Casiano, C.A., O'Brien, G.A., Fitzgerald, P., Tan, E.M., Bokoch, G.M., Greenberg, A.H. and Green, D.R. The cytotoxic cell protease granzyme B initiates apoptosis in a cell-free system by proteolytic processing and activation of the ICE/CED-3 family protease, CPP32, via a novel two-step mechanism. EMBO J. 15 (1996) 2407–2416. [PMID: 8665848]
[EC 3.4.22.56 created 2007]
 
 
EC 3.4.22.57     
Accepted name: caspase-4
Reaction: Strict requirement for Asp at the P1 position. It has a preferred cleavage sequence of Tyr-Val-Ala-Asp┼ but also cleaves at Asp-Glu-Val-Asp┼
Other name(s): ICErelII; ICErel-II; Ich-2; transcript X; TX; TX protease; caspase 4; CASP-4
Comments: This enzyme is part of the family of inflammatory caspases, which also includes caspase-1 (EC 3.4.22.36) and caspase-5 (EC 3.4.22.58) in humans and caspase-11 (EC 3.4.22.64), caspase-12, caspase-13 and caspase-14 in mice. Contains a caspase-recruitment domain (CARD) in its N-terminal prodomain, which plays a role in procaspase activation [3,5,6]. The enzyme is able to cleave itself and the p30 caspase-1 precursor, but, unlike caspase-1, it is very inefficient at generating mature interleukin-1β (IL-1β) from pro-IL-1β [1,4]. Both this enzyme and caspase-5 can cleave pro-caspase-3 to release the small subunit (p12) but not the large subunit (p17) [3]. The caspase-1 inhibitor Ac-Tyr-Val-Ala-Asp-CHO can also inhibit this enzyme, but more slowly [4]. Belongs in peptidase family C14.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, CAS registry number: 182762-08-9
References:
1.  Faucheu, C., Diu, A., Chan, A.W., Blanchet, A.M., Miossec, C., Hervé, F., Collard-Dutilleul, V., Gu, Y., Aldape, R.A., Lippke, J.A., Rocher, C., Su, M.S.-S., Livingston, D.J., Hercend, T. and Lalanne, J.-L. A novel human protease similar to the interleukin-1β converting enzyme induces apoptosis in transfected cells. EMBO J. 14 (1995) 1914–1922. [PMID: 7743998]
2.  Kamens, J., Paskind, M., Hugunin, M., Talanian, R.V., Allen, H., Banach, D., Bump, N., Hackett, M., Johnston, C.G., Li, P., Mankovich, J.A., Terranova, M. and Ghayur, T. Identification and characterization of ICH-2, a novel member of the interleukin-1β-converting enzyme family of cysteine proteases. J. Biol. Chem. 270 (1995) 15250–15256. [DOI] [PMID: 7797510]
3.  Kamada, S., Funahashi, Y. and Tsujimoto, Y. Caspase-4 and caspase-5, members of the ICE/CED-3 family of cysteine proteases, are CrmA-inhibitable proteases. Cell Death Differ. 4 (1997) 473–478. [DOI] [PMID: 16465268]
4.  Fassy, F., Krebs, O., Rey, H., Komara, B., Gillard, C., Capdevila, C., Yea, C., Faucheu, C., Blanchet, A.M., Miossec, C. and Diu-Hercend, A. Enzymatic activity of two caspases related to interleukin-1β-converting enzyme. Eur. J. Biochem. 253 (1998) 76–83. [DOI] [PMID: 9578463]
5.  Martinon, F. and Tschopp, J. Inflammatory caspases: linking an intracellular innate immune system to autoinflammatory diseases. Cell 117 (2004) 561–574. [DOI] [PMID: 15163405]
6.  Chang, H.Y. and Yang, X. Proteases for cell suicide: functions and regulation of caspases. Microbiol. Mol. Biol. Rev. 64 (2000) 821–846. [PMID: 11104820]
[EC 3.4.22.57 created 2007]
 
 
EC 3.4.22.58     
Accepted name: caspase-5
Reaction: Strict requirement for Asp at the P1 position. It has a preferred cleavage sequence of Tyr-Val-Ala-Asp┼ but also cleaves at Asp-Glu-Val-Asp┼
Other name(s): ICErel-III; Ich-3; ICH-3 protease; transcript Y; TY; CASP-5
Comments: This enzyme is part of the family of inflammatory caspases, which also includes caspase-1 (EC 3.4.22.36) and caspase-4 (EC 3.4.22.57) in humans and caspase-11 (EC 3.4.22.64), caspase-12, caspase-13 and caspase-14 in mice. Contains a caspase-recruitment domain (CARD) in its N-terminal prodomain, which plays a role in procaspase activation [3,5,6]. The enzyme is able to cleave itself and the p30 caspase-1 precursor, but is very inefficient at generating mature interleukin-1β (IL-1β) from pro-IL-1β [1,4]. Both this enzyme and caspase-4 can cleave pro-caspase-3 to release the small subunit (p12) but not the large subunit (p17) [3]. Unlike caspase-4, this enzyme can be induced by lipopolysaccharide [3]. Belongs in peptidase family C14.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, CAS registry number: 192465-11-5
References:
1.  Faucheu, C., Blanchet, A.M., Collard-Dutilleul, V., Lalanne, J.L. and Diu-Hercend, A. Identification of a cysteine protease closely related to interleukin-1 β-converting enzyme. Eur. J. Biochem. 236 (1996) 207–213. [DOI] [PMID: 8617266]
2.  Kamada, S., Funahashi, Y. and Tsujimoto, Y. Caspase-4 and caspase-5, members of the ICE/CED-3 family of cysteine proteases, are CrmA-inhibitable proteases. Cell Death Differ. 4 (1997) 473–478. [DOI] [PMID: 16465268]
3.  Lin, X.Y., Choi, M.S. and Porter, A.G. Expression analysis of the human caspase-1 subfamily reveals specific regulation of the CASP5 gene by lipopolysaccharide and interferon-γ. J. Biol. Chem. 275 (2000) 39920–39926. [DOI] [PMID: 10986288]
4.  Fassy, F., Krebs, O., Rey, H., Komara, B., Gillard, C., Capdevila, C., Yea, C., Faucheu, C., Blanchet, A.M., Miossec, C. and Diu-Hercend, A. Enzymatic activity of two caspases related to interleukin-1β-converting enzyme. Eur. J. Biochem. 253 (1998) 76–83. [DOI] [PMID: 9578463]
5.  Martinon, F. and Tschopp, J. Inflammatory caspases: linking an intracellular innate immune system to autoinflammatory diseases. Cell 117 (2004) 561–574. [DOI] [PMID: 15163405]
6.  Chang, H.Y. and Yang, X. Proteases for cell suicide: functions and regulation of caspases. Microbiol. Mol. Biol. Rev. 64 (2000) 821–846. [PMID: 11104820]
[EC 3.4.22.58 created 2007]
 
 
EC 3.4.22.59     
Accepted name: caspase-6
Reaction: Strict requirement for Asp at position P1 and has a preferred cleavage sequence of Val-Glu-His-Asp┼
Other name(s): CASP-6; apoptotic protease Mch-2; Mch2
Comments: Caspase-6 is an effector/executioner caspase, as are caspase-3 (EC 3.4.22.56) and caspase-7 (EC 3.4.22.60) [2]. These caspases are responsible for the proteolysis of the majority of cellular polypeptides [e.g. poly(ADP-ribose) polymerase (PARP)], which leads to the apoptotic phenotype [2]. Caspase-6 can cleave its prodomain to produce mature caspase-6, which directly activates caspase-8 (EC 3.4.22.61) and leads to the release of cytochrome c from the mitochondria. The release of cytochrome c is an essential component of the intrinsic apoptosis pathway [1]. The enzyme can also cleave and inactivate lamins, the intermediate filament scaffold proteins of the nuclear envelope, leading to nuclear fragmentation in the final phases of apoptosis [2,4,5,6]. Belongs in peptidase family C14.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, CAS registry number: 182372-15-2
References:
1.  Cowling, V. and Downward, J. Caspase-6 is the direct activator of caspase-8 in the cytochrome c-induced apoptosis pathway: absolute requirement for removal of caspase-6 prodomain. Cell Death Differ. 9 (2002) 1046–1056. [DOI] [PMID: 12232792]
2.  Chang, H.Y. and Yang, X. Proteases for cell suicide: functions and regulation of caspases. Microbiol. Mol. Biol. Rev. 64 (2000) 821–846. [PMID: 11104820]
3.  Kang, B.H., Ko, E., Kwon, O.K. and Choi, K.Y. The structure of procaspase 6 is similar to that of active mature caspase 6. Biochem. J. 364 (2002) 629–634. [DOI] [PMID: 12049625]
4.  Lee, S.C., Chan, J., Clement, M.V. and Pervaiz, S. Functional proteomics of resveratrol-induced colon cancer cell apoptosis: caspase-6-mediated cleavage of lamin A is a major signaling loop. Proteomics 6 (2006) 2386–2394. [DOI] [PMID: 16518869]
5.  MacLachlan, T.K. and El-Deiry, W.S. Apoptotic threshold is lowered by p53 transactivation of caspase-6. Proc. Natl. Acad. Sci. USA 99 (2002) 9492–9497. [DOI] [PMID: 12089322]
6.  Takahashi, A., Alnemri, E.S., Lazebnik, Y.A., Fernandes-Alnemri, T., Litwack, G., Moir, R.D., Goldman, R.D., Poirier, G.G., Kaufmann, S.H. and Earnshaw, W.C. Cleavage of lamin A by Mch2α but not CPP32: multiple interleukin 1β-converting enzyme-related proteases with distinct substrate recognition properties are active in apoptosis. Proc. Natl. Acad. Sci. USA 93 (1996) 8395–8400. [DOI] [PMID: 8710882]
[EC 3.4.22.59 created 2007]
 
 
EC 3.4.22.60     
Accepted name: caspase-7
Reaction: Strict requirement for an Asp residue at position P1 and has a preferred cleavage sequence of Asp-Glu-Val-Asp┼
Other name(s): CASP-7; ICE-like apoptotic protease 3; ICE-LAP3; apoptotic protease Mch-3; Mch3; CMH-1
Comments: Caspase-7 is an effector/executioner caspase, as are caspase-3 (EC 3.4.22.56) and caspase-6 (EC 3.4.22.59) [1]. These caspases are responsible for the proteolysis of the majority of cellular polypeptides [e.g. poly(ADP-ribose) polymerase (PARP)], which leads to the apoptotic phenotype [2]. Although a hydrophobic residue at P5 of caspase-2 (EC 3.4.22.55) and caspase-3 leads to more efficient hydrolysis, the amino-acid residue at this location in caspase-7 has no effect [3]. Caspase-7 is activated by the initiator caspases [caspase-8 (EC 3.4.22.61), caspase-9 (EC 3.4.22.62) and caspase-10 (EC 3.4.22.63)]. Removal of the N-terminal prodomain occurs before cleavage in the linker region between the large and small subunits [4]. Belongs in peptidase family C14.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, PDB, CAS registry number: 189258-14-8
References:
1.  Chang, H.Y. and Yang, X. Proteases for cell suicide: functions and regulation of caspases. Microbiol. Mol. Biol. Rev. 64 (2000) 821–846. [PMID: 11104820]
2.  Nicholson, D. and Thornberry, N.A. Caspase-3 and caspase-7. In: Barrett, A.J., Rawlings, N.D. and Woessner, J.F. (Eds), Handbook of Proteolytic Enzymes, 2nd edn, Elsevier, London, 2004, pp. 1298–1302.
3.  Fang, B., Boross, P.I., Tozser, J. and Weber, I.T. Structural and kinetic analysis of caspase-3 reveals role for S5 binding site in substrate recognition. J. Mol. Biol. 360 (2006) 654–666. [DOI] [PMID: 16781734]
4.  Denault, J.B. and Salvesen, G.S. Human caspase-7 activity and regulation by its N-terminal peptide. J. Biol. Chem. 278 (2003) 34042–34050. [DOI] [PMID: 12824163]
[EC 3.4.22.60 created 2007]
 
 
EC 3.4.22.61     
Accepted name: caspase-8
Reaction: Strict requirement for Asp at position P1 and has a preferred cleavage sequence of (Leu/Asp/Val)-Glu-Thr-Asp┼(Gly/Ser/Ala)
Other name(s): FLICE, FADD-like ICE; MACH; MORT1-associated CED-3 homolog; Mch5; mammalian Ced-3 homolog 5; CASP-8; ICE-like apoptotic protease 5; FADD-homologous ICE/CED-3-like protease; apoptotic cysteine protease; apoptotic protease Mch-5; CAP4
Comments: Caspase-8 is an initiator caspase, as are caspase-2 (EC 3.4.22.55), caspase-9 (EC 3.4.22.62) and caspase-10 (EC 3.4.22.63) [1]. Caspase-8 is the apical activator of the extrinsic (death receptor) apoptosis pathway, triggered by death receptor ligation [2]. It contains two tandem death effector domains (DEDs) in its N-terminal prodomain, and these play a role in procaspase activation [1]. This enzyme is linked to cell surface death receptors such as Fas [1,5]. When Fas is aggregated by the Fas ligand, procaspase-8 is recruited to the death receptor where it is activated [1]. The enzyme has a preference for Glu at P3 and prefers small residues, such as Gly, Ser and Ala, at the P1′ position. It has very broad P4 specificity, tolerating substrates with Asp, Val or Leu in this position [2,3,4]. Endogenous substrates for caspase-8 include procaspase-3, the pro-apoptotic Bcl-2 family member Bid, RIP, PAK2 and the caspase-8 activity modulator FLIPL [4,5]. Belongs in peptidase family C14.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, PDB, CAS registry number: 179241-78-2
References:
1.  Chang, H.Y. and Yang, X. Proteases for cell suicide: functions and regulation of caspases. Microbiol. Mol. Biol. Rev. 64 (2000) 821–846. [PMID: 11104820]
2.  Boldin, M.P., Goncharov, T.M., Goltsev, Y.V. and Wallach, D. Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death. Cell 85 (1996) 803–815. [DOI] [PMID: 8681376]
3.  Muzio, M., Chinnaiyan, A.M., Kischkel, F.C., O'Rourke, K., Shevchenko, A., Ni, J., Scaffidi, C., Bretz, J.D., Zhang, M., Gentz, R., Mann, M., Krammer, P.H., Peter, M.E. and Dixit, V.M. FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex. Cell 85 (1996) 817–827. [DOI] [PMID: 8681377]
4.  Salvesen, G.S. and Boatright, K.M. Caspase-8. In: Barrett, A.J., Rawlings, N.D. and Woessner, J.F. (Eds), Handbook of Proteolytic Enzymes, 2nd edn, Elsevier, London, 2004, pp. 1293–1296.
5.  Fischer, U., Stroh, C. and Schulze-Osthoff, K. Unique and overlapping substrate specificities of caspase-8 and caspase-10. Oncogene 25 (2006) 152–159. [DOI] [PMID: 16186808]
6.  Blanchard, H., Donepudi, M., Tschopp, M., Kodandapani, L., Wu, J.C. and Grütter, M.G. Caspase-8 specificity probed at subsite S(4): crystal structure of the caspase-8-Z-DEVD-cho complex. J. Mol. Biol. 302 (2000) 9–16. [DOI] [PMID: 10964557]
7.  Boatright, K.M., Deis, C., Denault, J.B., Sutherlin, D.P. and Salvesen, G.S. Activation of caspases-8 and -10 by FLIPL. Biochem. J. 382 (2004) 651–657. [DOI] [PMID: 15209560]
[EC 3.4.22.61 created 2007]
 
 
EC 3.4.22.62     
Accepted name: caspase-9
Reaction: Strict requirement for an Asp residue at position P1 and with a marked preference for His at position P2. It has a preferred cleavage sequence of Leu-Gly-His-Asp┼Xaa
Other name(s): CASP-9; ICE-like apoptotic protease 6; ICE-LAP6; apoptotic protease Mch-6; apoptotic protease-activating factor 3; APAF-3
Comments: Caspase-9 is an initiator caspase, as are caspase -2 (EC 3.4.22.55), caspase-8 (EC 3.4.22.61) and caspase-10 (EC 3.4.22.63) [1]. Caspase-9 contains a caspase-recruitment domain (CARD) in its N-terminal prodomain, which plays a role in procaspase activation [1]. An alternatively spliced version of caspase-9 also exists, caspase-9S, that inhibits apoptosis, similar to the situation found with caspase-2 [1]. Phosphorylation of caspase-9 from some species by Akt, a serine-threonine protein kinase, inhibits caspase activity in vitro and caspase activation in vivo [1]. The activity of caspase-9 is increased dramatically upon association with the apoptosome but the enzyme can be activated without proteolytic cleavage [2,3]. Procaspase-3 is the enzyme’s physiological substrate [2]. Belongs in peptidase family C14.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, PDB, CAS registry number: 180189-96-2
References:
1.  Chang, H.Y. and Yang, X. Proteases for cell suicide: functions and regulation of caspases. Microbiol. Mol. Biol. Rev. 64 (2000) 821–846. [PMID: 11104820]
2.  Yin, Q., Park, H.H., Chung, J.Y., Lin, S.C., Lo, Y.C., da Graca, L.S., Jiang, X. and Wu, H. Caspase-9 holoenzyme is a specific and optimal procaspase-3 processing machine. Mol. Cell. 22 (2006) 259–268. [DOI] [PMID: 16630893]
3.  Boatright, K.M., Renatus, M., Scott, F.L., Sperandio, S., Shin, H., Pedersen, I.M., Ricci, J.E., Edris, W.A., Sutherlin, D.P., Green, D.R. and Salvesen, G.S. A unified model for apical caspase activation. Mol. Cell. 11 (2003) 529–541. [DOI] [PMID: 12620239]
4.  Salvesen, G.S. and Boatright, K.M. Caspase-9. In: Barrett, A.J., Rawlings, N.D. and Woessner, J.F. (Eds), Handbook of Proteolytic Enzymes, 2nd edn, Elsevier, London, 2004, pp. 1296–1298.
[EC 3.4.22.62 created 2007]
 
 
EC 3.4.22.63     
Accepted name: caspase-10
Reaction: Strict requirement for Asp at position P1 and has a preferred cleavage sequence of Leu-Gln-Thr-Asp┼Gly
Other name(s): FLICE2, Mch4; CASP-10; ICE-like apoptotic protease 4; apoptotic protease Mch-4; FAS-associated death domain protein interleukin-1β-converting enzyme 2
Comments: Caspase-10 is an initiator caspase, as are caspase-2 (EC 3.4.22.55), caspase-8 (EC 3.4.22.61) and caspase-9 (EC 3.4.22.62) [1]. Like caspase-8, caspase-10 contains two tandem death effector domains (DEDs) in its N-terminal prodomain, and these play a role in procaspase activation [1]. The enzyme has many overlapping substrates in common with caspase-8, such as RIP (the cleavage of which impairs NF-κB survival signalling and starts the cell-death process) and PAK2 (associated with some of the morphological features of apoptosis, such as cell rounding and apoptotic body formation) [2]. Bid, a Bcl2 protein, can be cleaved by caspase-3 (EC 3.4.22.56), caspase-8 and caspase-10 at Lys-Gln-Thr-Asp┼ to yield the pro-apoptotic p15 fragment. The p15 fragment is N-myristoylated and enhances the release of cytochrome c from mitochondria (which, in turn, initiatiates the intrinsic apoptosis pathway). Bid can be further cleaved by caspase-10 and granzyme B but not by caspase-3 or caspase-8 at Ile-Glu-Thr-Asp┼ to yield a p13 fragment that is not N-myristoylated [2]. Belongs in peptidase family C14.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, CAS registry number: 189088-85-5
References:
1.  Chang, H.Y. and Yang, X. Proteases for cell suicide: functions and regulation of caspases. Microbiol. Mol. Biol. Rev. 64 (2000) 821–846. [PMID: 11104820]
2.  Fischer, U., Stroh, C. and Schulze-Osthoff, K. Unique and overlapping substrate specificities of caspase-8 and caspase-10. Oncogene 25 (2006) 152–159. [DOI] [PMID: 16186808]
3.  Shikama, Y., Yamada, M. and Miyashita, T. Caspase-8 and caspase-10 activate NF-κB through RIP, NIK and IKKα kinases. Eur. J. Immunol. 33 (2003) 1998–2006. [DOI] [PMID: 12884866]
4.  Boatright, K.M., Deis, C., Denault, J.B., Sutherlin, D.P. and Salvesen, G.S. Activation of caspases-8 and -10 by FLIPL. Biochem. J. 382 (2004) 651–657. [DOI] [PMID: 15209560]
[EC 3.4.22.63 created 2007]
 
 
EC 3.4.22.64     
Accepted name: caspase-11
Reaction: Strict requirement for Asp at the P1 position and has a preferred cleavage sequence of (Ile/Leu/Val/Phe)-Gly-His-Asp┼
Other name(s): CASP-11
Comments: This murine enzyme is part of the family of inflammatory caspases, which also includes caspase-1 (EC 3.4.22.36), caspase-4 (EC 3.4.22.57) and caspase-5 (EC 3.4.22.58) in humans and caspase-12, caspase-13 and caspase-14 in mice. Contains a caspase-recruitment domain (CARD) in its N-terminal prodomain, which plays a role in procaspase activation. Like caspase-5, but unlike caspase-4, this enzyme can be induced by lipopolysaccharide [1]. This enzyme not only activates caspase-1, which is required for the maturation of proinflammatory cytokines such as interleukin-1β (IL-1β) and IL-18, but it also activates caspase-3 (EC 3.4.22.56), which leads to cellular apoptosis under pathological conditions [1,2]. Belongs in peptidase family C14.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc
References:
1.  Kang, S.J., Wang, S., Hara, H., Peterson, E.P., Namura, S., Amin-Hanjani, S., Huang, Z., Srinivasan, A., Tomaselli, K.J., Thornberry, N.A., Moskowitz, M.A. and Yuan, J. Dual role of caspase-11 in mediating activation of caspase-1 and caspase-3 under pathological conditions. J. Cell. Biol. 149 (2000) 613–622. [PMID: 10791975]
2.  Hur, J., Kim, S.Y., Kim, H., Cha, S., Lee, M.S. and Suk, K. Induction of caspase-11 by inflammatory stimuli in rat astrocytes: lipopolysaccharide induction through p38 mitogen-activated protein kinase pathway. FEBS Lett. 507 (2001) 157–162. [DOI] [PMID: 11684090]
3.  Wang, S., Miura, M., Jung, Y.K., Zhu, H., Li, E. and Yuan, J. Murine caspase-11, an ICE-interacting protease, is essential for the activation of ICE. Cell 92 (1998) 501–509. [DOI] [PMID: 9491891]
4.  Endo, M., Mori, M., Akira, S. and Gotoh, T. C/EBP homologous protein (CHOP) is crucial for the induction of caspase-11 and the pathogenesis of lipopolysaccharide-induced inflammation. J. Immunol. 176 (2006) 6245–6253. [DOI] [PMID: 16670335]
5.  Chang, H.Y. and Yang, X. Proteases for cell suicide: functions and regulation of caspases. Microbiol. Mol. Biol. Rev. 64 (2000) 821–846. [PMID: 11104820]
[EC 3.4.22.64 created 2007]
 
 
EC 3.4.22.65     
Accepted name: peptidase 1 (mite)
Reaction: Broad endopeptidase specificity
Other name(s): allergen Der f 1; allergen Der p 1; antigen Der p 1; antigen Eur m 1; antigen Pso o 1; major mite fecal allergen Der p 1; Der p 1; Der f 1; Eur m 1; endopeptidase 1 (mite)
Comments: This enzyme, derived from the house dust mite, is a major component of the allergic immune response [2]. The substrate specificity of this enzyme is not altogether clear. It cleaves the low-affinity IgE receptor CD23 at Glu298┼Ser299 and Ser155┼Ser156 [1]. It also cleaves the pulmonary structural proteins occludin and claudin at Leu┼Leu, Asp┼Leu and at Gly┼Thr bonds [1,2]. It can also cleave the α subunit of the interleukin-2 (IL-2) receptor (CD25) [4]. Using a positional scanning combinatorial library, it was found that the major substrate-specificity determinant is for Ala in the P2 position [3]. The enzyme shows only a slight preference for basic amino acids in the P1 and P3 positions and a preference for aliphatic amino acids such as Ile, Pro, Val, Leu and norleucine in the P4 position [3]. Belongs in peptidase family C1A.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, PDB
References:
1.  Meighan, P. and Pirzad, R. Mite endopeptidase 1. In: Barrett, A.J., Rawlings, N.D. and Woessner, J.F. (Eds), Handbook of Proteolytic Enzymes, 2nd edn, Elsevier, London, 2004, pp. 1187–1189.
2.  Kalsheker, N.A., Deam, S., Chambers, L., Sreedharan, S., Brocklehurst, K. and Lomas, D.A. The house dust mite allergen Der p1 catalytically inactivates α1-antitrypsin by specific reactive centre loop cleavage: a mechanism that promotes airway inflammation and asthma. Biochem. Biophys. Res. Commun. 221 (1996) 59–61. [DOI] [PMID: 8660343]
3.  Harris, J., Mason, D.E., Li, J., Burdick, K.W., Backes, B.J., Chen, T., Shipway, A., Van Heeke, G., Gough, L., Ghaemmaghami, A., Shakib, F., Debaene, F. and Winssinger, N. Activity profile of dust mite allergen extract using substrate libraries and functional proteomic microarrays. Chem. Biol. 11 (2004) 1361–1372. [DOI] [PMID: 15489163]
4.  Schulz, O., Sewell, H.F. and Shakib, F. Proteolytic cleavage of CD25, the α subunit of the human T cell interleukin 2 receptor, by Der p 1, a major mite allergen with cysteine protease activity. J. Exp. Med. 187 (1998) 271–275. [PMID: 9432986]
5.  Schulz, O., Sewell, H.F. and Shakib, F. A sensitive fluorescent assay for measuring the cysteine protease activity of Der p 1, a major allergen from the dust mite Dermatophagoides pteronyssinus. Mol. Pathol. 51 (1998) 222–224. [PMID: 9893750]
6.  Takai, T., Kato, T., Sakata, Y., Yasueda, H., Izuhara, K., Okumura, K. and Ogawa, H. Recombinant Der p 1 and Der f 1 exhibit cysteine protease activity but no serine protease activity. Biochem. Biophys. Res. Commun. 328 (2005) 944–952. [DOI] [PMID: 15707969]
[EC 3.4.22.65 created 2007]
 
 
EC 3.4.22.66     
Accepted name: calicivirin
Reaction: Endopeptidase with a preference for cleavage when the P1 position is occupied by Glu┼ and the P1′ position is occupied by Gly┼
Other name(s): Camberwell virus processing peptidase; Chiba virus processing peptidase; Norwalk virus processing peptidase; Southampton virus processing peptidase; Southampton virus; norovirus virus processing peptidase; calicivirus trypsin-like cysteine protease; calicivirus TCP; calicivirus 3C-like protease; calicivirus endopeptidase; rabbit hemorrhagic disease virus 3C endopeptidase
Comments: Viruses that are members of the Norovirus genus (Caliciviridae family) are a major cause of epidemic acute viral gastroenteritis [4]. The nonstructural proteins of these viruses are produced by proteolytic cleavage of a large precursor polyprotein, performed by a protease that is incorporated into the polyprotein [6]. Cleavage sites are apparently defined by features based on both sequence and structure since several sites in the polyprotein fulfilling the identified sequence requirements are not cleaved [1]. The presence of acidic (Asp), basic (Arg), aromatic (Tyr) or aliphatic (Leu) amino acids at the P1′ position results in only minor differences in cleavage efficiency, suggesting that steric or conformational constraints may play a role in determining specificity [1]. Changes to the amino acid at the P2 position do not alter cleavage efficiency [1,2]. Belongs in peptidase family C37.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB
References:
1.  Meyers, G., Rossi, C. and Thiel, H.J. Calicivirus endopeptidases. In: Barrett, A.J., Rawlings, N.D. and Woessner, J.F. (Eds), Handbook of Proteolytic Enzymes, 2nd edn, Elsevier, London, 2004, pp. 1380–1382.
2.  Wirblich, C., Sibilia, M., Boniotti, M.B., Rossi, C., Thiel, H.J. and Meyers, G. 3C-like protease of rabbit hemorrhagic disease virus: identification of cleavage sites in the ORF1 polyprotein and analysis of cleavage specificity. J. Virol. 69 (1995) 7159–7168. [PMID: 7474137]
3.  Martín Alonso, J.M., Casais, R., Boga, J.A. and Parra, F. Processing of rabbit hemorrhagic disease virus polyprotein. J. Virol. 70 (1996) 1261–1265. [PMID: 8551592]
4.  Liu, B., Clarke, I.N. and Lambden, P.R. Polyprotein processing in Southampton virus: identification of 3C-like protease cleavage sites by in vitro mutagenesis. J. Virol. 70 (1996) 2605–2610. [PMID: 8642693]
5.  Liu, B.L., Viljoen, G.J., Clarke, I.N. and Lambden, P.R. Identification of further proteolytic cleavage sites in the Southampton calicivirus polyprotein by expression of the viral protease in E. coli. J. Gen. Virol. 80 (1999) 291–296. [DOI] [PMID: 10073687]
[EC 3.4.22.66 created 2007]
 
 
EC 3.4.22.67     
Accepted name: zingipain
Reaction: Preferential cleavage of peptides with a proline residue at the P2 position
Other name(s): ginger protease; GP-I; GP-II; ginger protease II (Zingiber officinale); zingibain
Comments: This enzyme is found in ginger (Zingiber officinale) rhizome and is a member of the papain family. GP-II contains two glycosylation sites. The enzyme is inhibited by some divalent metal ions, such as Hg2+, Cu2+, Cd2+ and Zn2+ [2]. Belongs in peptidase family C1.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, PDB
References:
1.  Choi, K.H. and Laursen, R.A. Amino-acid sequence and glycan structures of cysteine proteases with proline specificity from ginger rhizome Zingiber officinale. Eur. J. Biochem. 267 (2000) 1516–1526. [DOI] [PMID: 10691991]
2.  Ohtsuki, K., Taguchi, K., Sato, K. and Kawabata, M. Purification of ginger proteases by DEAE-Sepharose and isoelectric focusing. Biochim. Biophys. Acta 1243 (1995) 181–184. [DOI] [PMID: 7873561]
3.  Choi, K.H., Laursen, R.A. and Allen, K.N. The 2.1 Å structure of a cysteine protease with proline specificity from ginger rhizome, Zingiber officinale. Biochemistry 38 (1999) 11624–11633. [DOI] [PMID: 10512617]
[EC 3.4.22.67 created 2007]
 
 
EC 3.4.22.68     
Accepted name: Ulp1 peptidase
Reaction: Hydrolysis of the α-linked peptide bond in the sequence Gly-Gly┼Ala-Thr-Tyr at the C-terminal end of the small ubiquitin-like modifier (SUMO) propeptide, Smt3, leading to the mature form of the protein. A second reaction involves the cleavage of an ε-linked peptide bond between the C-terminal glycine of the mature SUMO and the lysine ε-amino group of the target protein
Other name(s): Smt3-protein conjugate proteinase; Ubl-specific protease 1; Ulp1; Ulp1 endopeptidase; Ulp1 protease
Comments: The enzyme from Saccharomyces cerevisiae can also recognize small ubiquitin-like modifier 1 (SUMO-1) from human as a substrate in both SUMO-processing (α-linked peptide bonds) and SUMO-deconjugation (ε-linked peptide bonds) reactions [1,2,3]. Ulp1 has several functions, including an essential role in chromosomal segregation and progression of the cell cycle through the G2/M phase of the cell cycle. Belongs in peptidase family C48.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, PDB
References:
1.  Lima, C.D. Ulp1 endopeptidase. In: Barrett, A.J., Rawlings, N.D. and Woessner, J.F. (Eds), Handbook of Proteolytic Enzymes, 2nd edn, Elsevier, London, 2004, pp. 1340–1344.
2.  Li, S.-J. and Hochstrasser, M. A new protease required for cell-cycle progression in yeast. Nature 398 (1999) 246–251. [DOI] [PMID: 10094048]
3.  Taylor, D.L., Ho, J.C., Oliver, A. and Watts, F.Z. Cell-cycle-dependent localisation of Ulp1, a Schizosaccharomyces pombe Pmt3 (SUMO)-specific protease. J. Cell Sci. 115 (2002) 1113–1122. [PMID: 11884512]
4.  Li, S.-J. and Hochstrasser, M. The Ulp1 SUMO isopeptidase: distinct domains required for viability, nuclear envelope localization, and substrate specificity. J. Cell Biol. 160 (2003) 1069–1081. [DOI] [PMID: 12654900]
5.  Ihara, M., Koyama, H., Uchimura, Y., Saitoh, H. and Kikuchi, A. Noncovalent binding of small ubiquitin-related modifier (SUMO) protease to SUMO is necessary for enzymatic activities and cell growth. J. Biol. Chem. 282 (2007) 16465–16475. [DOI] [PMID: 17428805]
6.  Mukhopadhyay, D. and Dasso, M. Modification in reverse: the SUMO proteases. Trends Biochem. Sci. 32 (2007) 286–295. [DOI] [PMID: 17499995]
[EC 3.4.22.68 created 2008, modified 2011]
 
 
EC 3.4.22.69     
Accepted name: SARS coronavirus main proteinase
Reaction: TSAVLQ┼SGFRK-NH2 and SGVTFQ┼GKFKK the two peptides corresponding to the two self-cleavage sites of the SARS 3C-like proteinase are the two most reactive peptide substrates. The enzyme exhibits a strong preference for substrates containing Gln at P1 position and Leu at P2 position.
Other name(s): 3cLpro; 3C-like protease; coronavirus 3C-like protease; Mpro; SARS 3C-like protease; SARS coronavirus 3CL protease; SARS coronavirus main peptidase; SARS coronavirus main protease; SARS-CoV 3CLpro enzyme; SARS-CoV main protease; SARS-CoV Mpro; severe acute respiratory syndrome coronavirus main protease
Comments: SARS coronavirus main protease is the key enzyme in SARS coronavirus replicase polyprotein processing. In peptidase family C30.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS
References:
1.  Goetz, D.H., Choe, Y., Hansell, E., Chen, Y.T., McDowell, M., Jonsson, C.B., Roush, W.R., McKerrow, J. and Craik, C.S. Substrate specificity profiling and identification of a new class of inhibitor for the major protease of the SARS coronavirus. Biochemistry 46 (2007) 8744–8752. [DOI] [PMID: 17605471]
2.  Fan, K., Wei, P., Feng, Q., Chen, S., Huang, C., Ma, L., Lai, B., Pei, J., Liu, Y., Chen, J. and Lai, L. Biosynthesis, purification, and substrate specificity of severe acute respiratory syndrome coronavirus 3C-like proteinase. J. Biol. Chem. 279 (2004) 1637–1642. [DOI] [PMID: 14561748]
3.  Akaji, K., Konno, H., Onozuka, M., Makino, A., Saito, H. and Nosaka, K. Evaluation of peptide-aldehyde inhibitors using R188I mutant of SARS 3CL protease as a proteolysis-resistant mutant. Bioorg. Med. Chem. 16 (2008) 9400–9408. [DOI] [PMID: 18845442]
[EC 3.4.22.69 created 2009]
 
 
EC 3.4.23.1     
Accepted name: pepsin A
Reaction: Preferential cleavage: hydrophobic, preferably aromatic, residues in P1 and P1′ positions. Cleaves Phe1┼Val, Gln4┼His, Glu13┼Ala, Ala14┼Leu, Leu15┼Tyr, Tyr16┼Leu, Gly23┼Phe, Phe24┼Phe and Phe25┼Tyr bonds in the B chain of insulin
Other name(s): pepsin; lactated pepsin; pepsin fortior; fundus-pepsin; elixir lactate of pepsin; P I; lactated pepsin elixir; P II; pepsin R; pepsin D
Comments: The predominant endopeptidase in the gastric juice of vertebrates, formed from pepsinogen A by limited proteolysis. Human pepsin A occurs in five molecular forms. Pig pepsin D [1,2] is unphosphorylated pepsin A. Type example of peptidase family A1.
Links to other databases: BRENDA, EXPASY, GTD, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 9001-75-6
References:
1.  Lee, D. and Ryle, A.P. Pepsinogen D. A fourth proteolytic zymogen from pig gastric mucosa. Biochem. J. 104 (1967) 735–741. [PMID: 4167464]
2.  Lee, D. and Ryle, A.P. Pepsin D. A minor component of commercial pepsin preparations. Biochem. J. 104 (1967) 742–748. [PMID: 4860638]
3.  Foltmann, R. Gastric proteinases -structure, function, evolution and mechanism of action. Essays Biochem. 17 (1981) 52–84. [PMID: 6795036]
4.  James, M.N.G. and Sielecki, A.R. Molecular structure of an aspartic proteinase zymogen, porcine pepsinogen, at 1.8 Å resolution. Nature 319 (1986) 33–38. [DOI] [PMID: 3941737]
5.  Fruton, J.S. Aspartyl proteinases. In: Neuberger, A. and Brocklehurst, K. (Eds), New Comprehensive Biochemistry: Hydrolytic Enzymes, vol. 16, Elsevier, Amsterdam, 1987, pp. 1–38.
6.  Tang, J. and Wong, R.N.S. Evolution in the structure and function of aspartic proteases. J. Cell. Biochem. 33 (1987) 53–63. [DOI] [PMID: 3546346]
7.  Pohl, J. and Dunn, B.M. Secondary enzyme-substrate interactions: kinetic evidence for ionic interactions between substrate side chains and the pepsin active site. Biochemistry 27 (1988) 4827–4834. [PMID: 3139029]
[EC 3.4.23.1 created 1961 as EC 3.4.4.1, transferred 1972 to EC 3.4.23.1, modified 1986, modified 1989]
 
 
EC 3.4.23.12     
Accepted name: nepenthesin
Reaction: Similar to pepsin, but also cleaves on either side of Asp and at Lys┼Arg
Other name(s): Nepenthes aspartic proteinase; Nepenthes acid proteinase; nepenthacin; nepenthasin; aspartyl endopeptidase
Comments: From the insectivorous plants Nepenthes spp. (secretions) and Drosera peltata (ground-up leaves). Aspartic endopeptidases are probably present in many other plants, including Lotus [3] and sorghum [2]. In peptidase family A1 (pepsin A family)
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, CAS registry number: 9073-80-7
References:
1.  Amagase, S., Nakayama, S. and Tsugita, A. Acid protease in Nepenthes. II. Study on the specificty of nepenthesin. J. Biochem. (Tokyo) 66 (1969) 431–439. [PMID: 5354017]
2.  Garg, G.K. and Virupaksha, T.K. Acid protease from germinated sorghum. 2. Substrate specificity with synthetic peptides and ribonuclease A. Eur. J. Biochem. 17 (1970) 4–12. [DOI] [PMID: 5486576]
3.  Shinano, S. and Fukushima, K. Studies on lotus seed protease. Part III. Some physicochemical and enzymic properties. Agric. Biol. Chem. 35 (1971) 1488–1494.
4.  Amagase, S. Digestive enzymes in insectivorous plants. III. Acid proteases in the genus Nepenthes and Drosera peltata. J. Biochem. (Tokyo) 72 (1972) 73–81. [PMID: 5069751]
5.  Takahashi, K., Chang, W-J. and Ko, J-S. Specific inhibition of acid proteases from brain, kidney, skeletal muscle, and insectivorous plants by diazoacetyl-DL-norleucine methyl ester and by pepstatin. J. Biochem. (Tokyo) 76 (1974) 897–899. [PMID: 4436292]
6.  Tökés, Z.A., Woon, W.C. and Chambers, S.M. Digestive enzymes secreted by the carnivorous plant Nepenthes macferlani L. Planta 119 (1974) 39–46. [DOI] [PMID: 16526095]
[EC 3.4.23.12 created 1972 as EC 3.4.99.4, transferred 1978 to EC 3.4.23.12, modified 1981]
 
 
EC 3.4.23.16     
Accepted name: HIV-1 retropepsin
Reaction: Specific for a P1 residue that is hydrophobic, and P1′ variable, but often Pro
Other name(s): human immunodeficiency virus type 1 protease; gag protease; HIV aspartyl protease; HIV proteinase; retroproteinase; HIV-1 protease; HIV-2 protease
Comments: Present in human immunodeficiency virus type 1. Contributes to the maturation of the viral particle, and is a target of antiviral drugs. Active enzyme is a dimer of identical 11-kDa subunits. Similar enzymes occur in other retroviruses [1]. Type example of peptidase family A2
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 144114-21-6
References:
1.  Kuo, L.C. and Shafer, J.A. (eds) Retroviral Proteases. Methods Enzymol. 241 (1994) 1–431.
2.  Dunn, B.M. Human immunodeficiency virus 1 retropepsin. In: Barrett, A.J., Rawlings, N.D. and Woessner, J.F. (Eds), Handbook of Proteolytic Enzymes, Academic Press, London, 1998, pp. 919–928.
[EC 3.4.23.16 created 1992, modified 2000]
 
 
EC 3.4.23.17     
Accepted name: pro-opiomelanocortin converting enzyme
Reaction: Cleavage at paired basic residues in certain prohormones, either between them, or on the carboxyl side
Other name(s): prohormone converting enzyme; pro-opiomelanocortin-converting enzyme; proopiomelanocortin proteinase; PCE
Comments: A 70 kDa membrane-bound enzyme isolated from cattle pituitary secretory vesicle.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, CAS registry number: 80891-34-5
References:
1.  Loh, Y.P., Parish, D.C. and Tuteja, R. Purification and characterization of a paired basic residue-specific pro-opiomelanocortin converting enzyme from bovine pituitary intermediate lobe secretory vesicles. J. Biol. Chem. 260 (1985) 7194–7205. [PMID: 2987247]
2.  Loh, Y.P. Kinetic studies on the processing of human β-lipotropin by bovine pituitary intermediate lobe pro-opiomelanocortin-converting enzyme. J. Biol. Chem. 261 (1986) 11949–11955. [PMID: 3017955]
3.  Estivariz, F.E., Birch, N.P. and Loh, Y.P. Generation of Lys-γ3-melanotropin from pro-opiomelanocortin1-77 by a bovine intermediate lobe secretory vesicle membrane-associated aspartic protease and purified pro-opiomelanocortin converting enzyme. J. Biol. Chem. 264 (1989) 17796–17801. [PMID: 2553692]
[EC 3.4.23.17 created 1989 as EC 3.4.99.38, transferred 1992 to EC 3.4.23.17]
 
 
EC 3.4.23.18     
Accepted name: aspergillopepsin I
Reaction: Hydrolysis of proteins with broad specificity. Generally favours hydrophobic residues in P1 and P1′, but also accepts Lys in P1, which leads to activation of trypsinogen. Does not clot milk
Other name(s): Aspergillus acid protease; Aspergillus acid proteinase; Aspergillus aspartic proteinase; Aspergillus awamori acid proteinase; Aspergillus carboxyl proteinase; (see also Comments); carboxyl proteinase; Aspergillus kawachii aspartic proteinase; Aspergillus saitoi acid proteinase; pepsin-type aspartic proteinase; Aspergillus niger acid proteinase; sumizyme AP; proctase P; denapsin; denapsin XP 271; proctase
Comments: Found in a variety of Aspergillus species (imperfect fungi): Aspergillus awamori (awamorin, aspergillopepsin A: [8]), A. foetidus (aspergillopepsin F: [6]), A. fumigatus [7], A. kawachii [9], A. niger (proteinase B, proctase B: [2,4]), A. oryzae (trypsinogen kinase: [3,10]), A. saitoi (aspergillopeptidase A: [10]), and A. sojae [5,10]. In peptidase family A1 (pepsin A family). Formerly included in EC 3.4.23.6
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 9025-49-4
References:
1.  Kovaleva, G.G., Shimanskaya, M.P. and Stepanov, V.M. The site of diazoacetyl inhibitor attachment to acid proteinase of Aspergillus awamori - an analog of penicillopepsin and pepsin. Biochem. Biophys. Res. Commun. 49 (1972) 1075–1082. [DOI] [PMID: 4565799]
2.  Morihara, K. and Oka, T. Comparative specificity of microbial acid proteinases for synthetic peptides. III. Relationship with their trypsinogen activating ability. Arch. Biochem. Biophys. 157 (1973) 561–572. [PMID: 4593189]
3.  Davidson, R., Gertler, A. and Hofmann, T. Aspergillus oryzae acid proteinase. Purification and properties, and formation of π-chymotrypsin. Biochem. J. 147 (1975) 45–53. [PMID: 239702]
4.  Chang, W.-J., Horiuchi, S., Takahashi, K., Yamasaki, M. and Yamada, Y. The structure and function of acid proteases. VI. Effects of acid protease-specific inhibitors on the acid proteases from Aspergillus niger var. macrosporus. J. Biochem. (Tokyo) 80 (1976) 975–981. [PMID: 12156]
5.  Tanaka, N., Takeuchi, M. and Ichishima, E. Purification of an acid proteinase from Aspergillus saitoi and determination of peptide bond specificity. Biochim. Biophys. Acta 485 (1977) 406–416. [DOI] [PMID: 21699]
6.  Ostoslavskaya, V.I., Kotlova, E.K., Stepanov, V.M., Rudenskaya, G.H., Baratova, L.A. and Belyanova, L.P. Aspergillopepsin F-A carboxylic proteinase from Aspergillus foetidus. Bioorg. Khim. 5 (1976) 595–603.
7.  Panneerselvam, M. and Dhar, S.C. Studies on the peptide bond specificity and the essential groups of an acid proteinase from Aspergillus fumigatus. Ital. J. Biochem. 30 (1981) 207–216. [PMID: 7024192]
8.  Ostoslavskaya, V.I., Revina, L.P., Kotlova, E.K., Surova, I.A., Levin, E.D., Timokhima, E.A. and Stepanov, V.M. The primary structure of aspergillopepsin A, aspartic proteinase from Aspergillus awamori. IV. Amino acid sequence of the enzyme. Bioorg. Khim. 12 (1986) 1030–1047.
9.  Yagi, F., Fan, J., Tadera, K. and Kobayashi, A. Purification and characterization of carboxyl proteinase from Aspergillus kawachii. Agric. Biol. Chem. 50 (1986) 1029–1033.
10.  Majima, E., Oda, K., Murao, S. and Ichishima, E. Comparative study on the specificities of several fungal aspartic and acidic proteinases towards the tetradecapeptide of a renin substrate. Agric. Biol. Chem. 52 (1988) 787–793.
[EC 3.4.23.18 created 1992 (EC 3.4.23.6 created 1961 as EC 3.4.4.17, transferred 1972 to EC 3.4.23.6, modified 1981 [EC 3.4.23.7, EC 3.4.23.8, EC 3.4.23.9, EC 3.4.23.10, EC 3.4.99.1, EC 3.4.99.15 and EC 3.4.99.25 all created 1972 and incorporated 1978], part incorporated 1992)]
 
 
EC 3.4.23.19     
Accepted name: aspergillopepsin II
Reaction: Preferential cleavage in B chain of insulin: Asn3┼Gln, Gly13┼Ala, Tyr26┼Thr
Other name(s): proteinase A; proctase A; Aspergillus niger var. macrosporus aspartic proteinase
Comments: Isolated from Aspergillus niger var. macrosporus, distinct from proteinase B (see aspergillopepsin I) in specificity and insensitivity to pepstatin. In peptidase family A4 (scytalidopepsin B family). Formerly included in EC 3.4.23.6
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 9025-49-4
References:
1.  Chang, W.-J., Horiuchi, S., Takahashi, K., Yamasaki, M. and Yamada, Y. The structure and function of acid proteases. VI. Effects of acid protease-specific inhibitors on the acid proteases from Aspergillus niger var. macrosporus. J. Biochem. (Tokyo) 80 (1976) 975–981. [PMID: 12156]
2.  Iio, K. and Yamasaki, M. Specificity of acid proteinase A from Aspergillus niger var. macrosporus towards B-chain of performic acid oxidized bovine insulin. Biochim. Biophys. Acta 429 (1976) 912–924. [DOI] [PMID: 1268233]
[EC 3.4.23.19 created 1992 (EC 3.4.23.6 created 1992 (EC 3.4.23.6 created 1961 as EC 3.4.4.17, transferred 1972 to EC 3.4.23.6, modified 1981 [EC 3.4.23.7, EC 3.4.23.8, EC 3.4.23.9, EC 3.4.23.10, EC 3.4.99.1, EC 3.4.99.15 and EC 3.4.99.25 all created 1972 and incorporated 1978], part incorporated 1992)]
 
 
EC 3.4.23.20     
Accepted name: penicillopepsin
Reaction: Hydrolysis of proteins with broad specificity similar to that of pepsin A, preferring hydrophobic residues at P1 and P1′, but also cleaving Gly20┼Glu in the B chain of insulin. Clots milk, and activates trypsinogen
Other name(s): peptidase A; Penicillium janthinellum aspartic proteinase; acid protease A; Penicillium citrinum acid proteinase; Penicillium cyclopium acid proteinase; Penicillium expansum acid proteinase; Penicillium janthinellum acid proteinase; Penicillium expansum aspartic proteinase; Penicillium aspartic proteinase; Penicillium caseicolum aspartic proteinase; Penicillium roqueforti acid proteinase; Penicillium duponti aspartic proteinase; Penicillium citrinum aspartic proteinase
Comments: From the imperfect fungus Penicillium janthinellum. In peptidase family A1 (pepsin A family). Closely related enzymes have been isolated from P. roqueforti [2] and P. duponti [3].
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 9074-08-2
References:
1.  Mains, G., Takahashi, M., Sodek, J. and Hofmann, T. The specificity of penicillopepsin. Can. J. Biochem. 49 (1971) 1134–1149. [PMID: 4946839]
2.  Zevaco, C., Hermier, J. and Gripon, J.-C. Le système protéolytique de Penicillium roqueforti. II - Purification et propriétés de la protéase acide. Biochimie 55 (1973) 1353–1360. [PMID: 4790849]
3.  Emi, S., Myers, D.V. and Iacobucci, G.A. Purification and properties of the thermostable acid protease of Penicillium duponti. Biochemistry 15 (1976) 842–848. [PMID: 2287]
4.  Hofmann, T. Penicillopepsin. Methods Enzymol. 45 (1976) 434–450. [DOI] [PMID: 1012008]
5.  Hsu, I.-N., Delbaere, L.T.J., James, M.N.G. and Hofmann, T. Penicillopepsin from Penicillium janthinellum crystal structure at 2.8 Å and sequence homology with porcine pepsin. Nature 266 (1977) 140–144. [PMID: 323722]
[EC 3.4.23.20 created 1992 (EC 3.4.23.6 created 1992 (EC 3.4.23.6 created 1961 as EC 3.4.4.17, transferred 1972 to EC 3.4.23.6, modified 1981 [EC 3.4.23.7, EC 3.4.23.8, EC 3.4.23.9, EC 3.4.23.10, EC 3.4.99.1, EC 3.4.99.15 and EC 3.4.99.25 all created 1972 and incorporated 1978], part incorporated 1992)]
 
 
EC 3.4.23.21     
Accepted name: rhizopuspepsin
Reaction: Hydrolysis of proteins with broad specificity similar to that of pepsin A, preferring hydrophobic residues at P1 and P1′. Clots milk and activates trypsinogen. Does not cleave Gln4-His, but does cleave His10┼Leu and Val12┼Glu in B chain of insulin
Other name(s): Rhizopus aspartic proteinase; neurase; Rhizopus acid protease; Rhizopus acid proteinase
Comments: From the zygomycete fungus Rhizopus chinensis. A similar endopeptidase is found in R. niveus [2]. In peptidase family A1 (pepsin A family).
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 9074-09-3
References:
1.  Tsuru, D., Hattori, A., Tsuji, H., Yamamoto, T. and Fukumoto, J. Studies on mold proteases. Part II. Substrate specificity of acid protease of Rhizopus chinensis. Agric. Biol. Chem. 33 (1969) 1419–1426.
2.  Kurono, Y., Chidimatsu, M., Horikoshi, K. and Ikeda, Y. Isolation of a protease from a Rhizopus product. Agric. Biol. Chem. 35 (1971) 1668–1675.
3.  Ohtsuru, M., Tang, J. and Delaney, R. Purification and characterization of rhizopuspesin isozymes from a liquid culture of Rhizopus chinensis. Int. J. Biochem. 14 (1982) 925–932. [PMID: 6751894]
4.  Suguna, K., Padlan, E.A., Smith, C.W., Carlson, W.D. and Davies, D.R. Binding of a reduced peptide inhibitor to the aspartic proteinase from Rhizopus chinensis: implications for a mechanism of action. Proc. Natl. Acad. Sci. USA 84 (1987) 7009–7013. [DOI] [PMID: 3313384]
[EC 3.4.23.21 created 1992 (EC 3.4.23.6 created 1992 (EC 3.4.23.6 created 1961 as EC 3.4.4.17, transferred 1972 to EC 3.4.23.6, modified 1981 [EC 3.4.23.7, EC 3.4.23.8, EC 3.4.23.9, EC 3.4.23.10, EC 3.4.99.1, EC 3.4.99.15 and EC 3.4.99.25 all created 1972 and incorporated 1978], part incorporated 1992)]
 
 
EC 3.4.23.22     
Accepted name: endothiapepsin
Reaction: Hydrolysis of proteins with specificity similar to that of pepsin A; prefers hydrophobic residues at P1 and P1′, but does not cleave Ala14-Leu in the B chain of insulin or Z-Glu-Tyr. Clots milk
Other name(s): Endothia aspartic proteinase; Endothia acid proteinase; Endothia parasitica acid proteinase; Endothia parasitica aspartic proteinase
Comments: From the ascomycete Endothia parasitica. In peptidase family A1 (pepsin A family).
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 37205-60-0
References:
1.  Whitaker, J.R. Protease of Endothia parasitica. Methods Enzymol. 19 (1970) 436–445.
2.  Williams, D.C., Whitaker, J.R. and Caldwell, P.V. Hydrolysis of peptide bonds of the oxidized B-chain of insulin by Endothia parasitica protease. Arch. Biochem. Biophys. 149 (1972) 52–61. [DOI] [PMID: 4552802]
3.  Barkholt, V. Amino acid sequence of endothiapepsin. Complete primary structure of the aspartic protease from Endothia parasitica. Eur. J. Biochem. 167 (1987) 327–338. [DOI] [PMID: 3305016]
4.  Cooper, J., Foundling, S., Hemmings, A., Blundell, T., Jones, D.M., Hallett, A. and Szelke, M. The structure of a synthetic pepsin inhibitor complexed with endothiapepsin. Eur. J. Biochem. 169 (1987) 215–221. [DOI] [PMID: 3119339]
[EC 3.4.23.22 created 1992 (EC 3.4.23.6 created 1992 (EC 3.4.23.6 created 1961 as EC 3.4.4.17, transferred 1972 to EC 3.4.23.6, modified 1981 [EC 3.4.23.7, EC 3.4.23.8, EC 3.4.23.9, EC 3.4.23.10, EC 3.4.99.1, EC 3.4.99.15 and EC 3.4.99.25 all created 1972 and incorporated 1978], part incorporated 1992)]
 
 
EC 3.4.23.23     
Accepted name: mucorpepsin
Reaction: Hydrolysis of proteins, favouring hydrophobic residues at P1 and P1′. Clots milk. Does not accept Lys at P1, and hence does not activate trypsinogen
Other name(s): Mucor rennin; Mucor aspartic proteinase; Mucor acid proteinase; Mucor acid protease; Mucor miehei aspartic proteinase; Mucor miehei aspartic protease; Mucor aspartic proteinase; Mucor pusillus emporase; Fromase 100; Mucor pusillus rennin; Fromase 46TL; Mucor miehei rennin
Comments: Isolated from the zygomycete fungi Mucor pusillus and M. miehei. The two species variants show 83% sequence identity and are immunologically crossreactive. In peptidase family A1 (pepsin A family). Formerly included in EC 3.4.23.6
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 148465-73-0
References:
1.  Arima, K., Yu, J. and Iwasaki, S. Milk-clotting enzyme from Mucor pusillus var. lindt. Methods Enzymol. 19 (1970) 446–459.
2.  Ottesen, M. and Rickert, W. The acid protease of Mucor miehei. Methods Enzymol. 19 (1970) 459–460.
3.  Sternberg, M. Bond specificity, active site and milk cloting mechanism of the Mucor miehei protease. Biochim. Biophys. Acta 285 (1972) 383–392. [DOI] [PMID: 4573298]
4.  Oka, T., Ishino, K., Tsuzuki, H., Morihara, K. and Arima, K. On the specificity of a rennin-like enzyme from Mucor pusillus. Agric. Biol. Chem. 37 (1973) 1177–1184.
5.  Baudy, M., Foundling, S., Pavlik, M., Blundell, T. and Kostka, V. Protein chemical characterization of Mucor pusillus aspartic proteinase. Amino acid sequence homology with the other aspartic proteinases, disulfide bond arrangement and site of carbohydrate attachment. FEBS Lett. 235 (1988) 271–274. [DOI] [PMID: 3042459]
[EC 3.4.23.23 created 1992 (EC 3.4.23.6 created 1992 (EC 3.4.23.6 created 1961 as EC 3.4.4.17, transferred 1972 to EC 3.4.23.6, modified 1981 [EC 3.4.23.7, EC 3.4.23.8, EC 3.4.23.9, EC 3.4.23.10, EC 3.4.99.1, EC 3.4.99.15 and EC 3.4.99.25 all created 1972 and incorporated 1978], part incorporated 1992)]
 
 
EC 3.4.23.26     
Accepted name: rhodotorulapepsin
Reaction: Specificity similar to that of pepsin A. Cleaves Z-Lys┼Ala-Ala-Ala and activates trypsinogen
Other name(s): Rhodotorula aspartic proteinase; Cladosporium acid protease; Cladosporium acid proteinase; Paecilomyces proteinase; Cladosporium aspartic proteinase; Paecilomyces proteinase; Rhodotorula glutinis aspartic proteinase; Rhodotorula glutinis acid proteinase; Rhodotorula glutinis aspartic proteinase II; Rhodotorula acid proteinase
Comments: From the imperfect yeast Rhodotorula glutinis. Somewhat similar enzymes have been isolated from the imperfect yeast-like organism Cladosporium sp. [4,6] and the imperfect fungus Paecilomyces varioti [1,2].
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, CAS registry number: 37259-59-9
References:
1.  Sawada, J. Studies on the acid-protease of Paecilomyces varioti Bainier TPR-220. Part I. Crystallization of the acid-protease of Paecilomyces varioti Bainier TPR-220. Agric. Biol. Chem. 27 (1963) 677–683.
2.  Sawada, J. The acid-protease of Paecilomyces varioti. III. The specificity of the crystalline acid-protease on synthetic substrates. Agric. Biol. Chem. 28 (1964) 869–875.
3.  Kamada, M., Oda, K. and Murao, S. The purification of the extracellular acid protease of Rhodotorula glutinis K-24 and its general properties. Agric. Biol. Chem. 36 (1972) 1095–1101.
4.  Murao, S., Funakoshi, S. and Oda, K. Purification, crystallization and some enzymatic properties of acid protease of Cladosporium sp. No. 45-2. Agric. Biol. Chem. 36 (1972) 1327–1333.
5.  Oda, K., Kamada, M. and Murao, S. Some physicochemical properties and substrate specificity of acid protease of Rhodotorula glutinis K-24. Agric. Biol. Chem. 36 (1972) 1103–1108.
6.  Oda, K., Funakoshi, S. and Murao, S. Some physicochemical properties and substrate specificity of acid protease isolated from Cladosporium sp. No. 45-2. Agric. Biol. Chem. 37 (1973) 1723–1729.
7.  Takahashi, K. and Chang, W.-J. The structure and function of acid proteases. V. Comparative studies on the specific inhibition of acid proteases by diazoacetyl-DL-norleucine methyl ester, 1,2-epoxy-3-(p-nitrophenoxy)propane and pepstatin. J. Biochem. (Tokyo) 80 (1976) 497–506. [PMID: 10290]
8.  Majima, E., Oda, K., Murao, S. and Ichishima, E. Comparative study on the specificities of several fungal aspartic and acidic proteinases towards the tetradecapeptide of a renin substrate. Agric. Biol. Chem. 52 (1988) 787–793.
[EC 3.4.23.26 created 1992 (EC 3.4.23.6 created 1992 (EC 3.4.23.6 created 1961 as EC 3.4.4.17, transferred 1972 to EC 3.4.23.6, modified 1981 [EC 3.4.23.7, EC 3.4.23.8, EC 3.4.23.9, EC 3.4.23.10, EC 3.4.99.1, EC 3.4.99.15 and EC 3.4.99.25 all created 1972 and incorporated 1978], part incorporated 1992)]
 
 
EC 3.4.23.28     
Accepted name: acrocylindropepsin
Reaction: Preference for hydrophobic residues at P1 and P1′. Action on the B chain of insulin is generally similar to that of pepsin A, but it also cleaves Leu6┼Cys(SO3H), Glu21┼Arg and Asn3┼Gln, although not Gln4-His
Other name(s): Acrocylindrium proteinase; Acrocylindrium acid proteinase
Comments: From the imperfect fungus Acrocylindrium sp. Has a very low pH optimum on casein of 2.0. In peptidase family A1 (pepsin A family).
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, CAS registry number: 37288-84-9
References:
1.  Uchino, F., Kurono, Y. and Doi, S. Purification and some properties of crystalline acid protease from Acrocylindrium sp. Agric. Biol. Chem. 31 (1967) 428–434.
2.  Ichihara, S. and Uchino, F. The specificity of acid proteinase from Acrocylindrium. Agric. Biol. Chem. 39 (1975) 423–428.
3.  Takahashi, K. and Chang, W.-J. The structure and function of acid proteases. V. Comparative studies on the specific inhibition of acid proteases by diazoacetyl-DL-norleucine methyl ester, 1,2-epoxy-3-(p-nitrophenoxy)propane and pepstatin. J. Biochem. (Tokyo) 80 (1976) 497–506. [PMID: 10290]
[EC 3.4.23.28 created 1992 (EC 3.4.23.6 created 1992 (EC 3.4.23.6 created 1961 as EC 3.4.4.17, transferred 1972 to EC 3.4.23.6, modified 1981 [EC 3.4.23.7, EC 3.4.23.8, EC 3.4.23.9, EC 3.4.23.10, EC 3.4.99.1, EC 3.4.99.15 and EC 3.4.99.25 all created 1972 and incorporated 1978], part incorporated 1992)]
 
 
EC 3.4.23.30     
Accepted name: pycnoporopepsin
Reaction: Similar to pepsin A, but narrower, cleaving only three bonds in the B chain of insulin: Ala14┼Leu, Tyr16┼Leu, and Phe24┼Phe
Other name(s): proteinase Ia; Pycnoporus coccineus aspartic proteinase; Trametes acid proteinase
Comments: From the basidiomycete Pycnoporus sanguineus, formerly known as P. coccineus and Trametes sanguinea. Formerly included in EC 3.4.23.6
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, CAS registry number: 77967-78-3
References:
1.  Tomoda, K. and Shimazono, H. Acid protease produced by Trametes sanguinea a wood-destroying fungus. Part I. Purification and crystallization of the enzyme. Agric. Biol. Chem. 28 (1964) 770–773.
2.  Tsuru, D., Hattori, A., Tsuji, H., Yamamoto, T. and Fukumoto, J. Studies on mold proteases. Part II. Substrate specificity of acid protease of Rhizopus chinensis. Agric. Biol. Chem. 33 (1969) 1419–1426.
3.  Ichishima, E., Kumagai, H. and Tomoda, K. Substrate specificity of carboxyl proteinase from Pycnoporus coccineus, a wood-deteriorating fungus. Curr. Microbiol. 3 (1980) 333–337.
[EC 3.4.23.30 created 1992 (EC 3.4.23.6 created 1992 (EC 3.4.23.6 created 1961 as EC 3.4.4.17, transferred 1972 to EC 3.4.23.6, modified 1981 [EC 3.4.23.7, EC 3.4.23.8, EC 3.4.23.9, EC 3.4.23.10, EC 3.4.99.1, EC 3.4.99.15 and EC 3.4.99.25 all created 1972 and incorporated 1978], part incorporated 1992)]
 
 
EC 3.4.23.31     
Accepted name: scytalidopepsin A
Reaction: Hydrolysis of proteins with specificity similar to that of pepsin A, but also cleaves Cys(SO3H)7┼Gly and Leu17┼Val in the B chain of insulin
Other name(s): Scytalidium aspartic proteinase A; Scytalidium lignicolum aspartic proteinase; Scytalidium lignicolum aspartic proteinase A-2; Scytalidium lignicolum aspartic proteinase A-I; Scytalidium lignicolum aspartic proteinase C; Scytalidium lignicolum carboxyl proteinase; Scytalidium lignicolum acid proteinase
Comments: Isolated from the imperfect fungus Scytalidium lignicolum. Not inhibited by pepstatin-Ac, methyl 2-diazoacetamidohexanoate or 1,2-epoxy-3-(p-nitrophenyl)propane. A related enzyme from the same organism, proteinase C, is also insensitive to these inhibitors and has Mr = 406,000 [3]
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, CAS registry number: 42613-34-3
References:
1.  Oda, K. and Murao, S. Purification and some enzymatic properties of acid protease A and B of Scytalidium lignicolum ATCC 24568. Agric. Biol. Chem. 38 (1974) 2435–2444.
2.  Oda, K. and Murao, S. Action of Scytalidium lignicolum acid proteases on insulin B-chain. Agric. Biol. Chem. 40 (1976) 1221–1225.
3.  Oda, K., Torishima, H. and Murao, S. Purification and characterization of acid proteinase C of Scytalidium lignicolum ATCC 24568. Agric. Biol. Chem. 50 (1986) 651–658.
[EC 3.4.23.31 created 1992]
 
 
EC 3.4.23.32     
Accepted name: scytalidopepsin B
Reaction: Hydrolysis of proteins with broad specificity, cleaving Phe24┼Phe, but not Leu15-Tyr and Phe25-Tyr in the B chain of insulin
Other name(s): Scytalidium aspartic proteinase B; Ganoderma lucidum carboxyl proteinase; Ganoderma lucidum aspartic proteinase; Scytalidium lignicolum aspartic proteinase B; SLB
Comments: A second endopeptidase from Scytalidium lignicolum (see scytalidopepsin A) that is insensitive to pepstatin and methyl 2-diazoacetamidohexanoate. 1,2-Epoxy-3-(p-nitrophenoxy)propane reacts with Glu53, which replaces one of the aspartic residues at the active centre. One of the smallest aspartic endopeptidases active as the monomer, with Mr 22,000. Similarly inhibitor-resistant endopeptidases are found in the basidiomycetes Lentinus edodes [1] and Ganoderma lucidum [3], and in Polyporus tulipiferae [4], a second endopeptidase distinct from polyporopepsin, but these are of typical aspartic endopeptidase size, Mr about 36,000. Type example of peptidase family G1.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 104781-89-7
References:
1.  Terashita, T., Oda, K., Kono, M. and Murao, S. Streptomyces pepsin inhibitor-insensitive carboxyl proteinase from Lentinus edodes. Agric. Biol. Chem. 45 (1981) 1937–1943.
2.  Maita, T., Nagata, S., Matsuda, G., Maruta, S., Oda, K., Murao, S. and Tsuru, D. Complete amino acid sequence of Scytalidium lignicolum acid protease B. J. Biochem. (Tokyo) 95 (1984) 465–473. [PMID: 6370989]
3.  Terashita, T., Oda, K., Kono, M. and Murao, S. Streptomyces pepsin inhibitor-insensitive carboxyl proteinase from Ganoderma lucidum. Agric. Biol. Chem. 48 (1984) 1029–1035.
4.  Kobayashi, H., Kusakabe, I. and Murakami, K. Purification and characterization of a pepstatin-insensitive carboxyl proteinase from Polyporus tulipiferae (Irpex lacteus). Agric. Biol. Chem. 49 (1985) 2393–2397.
5.  Tsuru, D., Shimada, S., Maruta, S., Yoshimoto, T., Oda, K., Murao, S., Miyata, T. and Iwanaga, S. Isolation and amino acid sequence of a peptide containing an epoxide-reactive residue from the thermolysin-digest of Scytalidium lignicolum acid protease B. J. Biochem. (Tokyo) 99 (1986) 1537–1539. [PMID: 3519605]
[EC 3.4.23.32 created 1992]
 
 
EC 3.4.23.38     
Accepted name: plasmepsin I
Reaction: Hydrolysis of the -Phe33┼Leu- bond in the α-chain of hemoglobin, leading to denaturation of the molecule
Other name(s): aspartic hemoglobinase I; PFAPG; malaria aspartic hemoglobinase
Comments: Known from the malaria organism, Plasmodium. About 37 kDa. In peptidase family A1 (pepsin A family), closest to cathepsin D and renin in structure. Inhibited by pepstatin. Formerly included in EC 3.4.23.6
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 180189-87-1
References:
1.  Goldberg, D.E., Slater, A.F.G., Beavis, R., Chait, B., Cerami, A. and Henderson, G.B. Hemoglobin degradation in the human malaria pathogen Plasmodium falciparum: a catabolic pathway initiated by a specific aspartic protease. J. Exp. Med. 173 (1991) 961–969. [PMID: 2007860]
2.  Francis, S.E., Gluzman, I.Y., Oksman, A., Knickerbocker, A., Mueller, R., Bryant, M.L., Sherman, D.R., Russell, D.G. and Goldberg, D.E. Molecular characterization and inhibition of a Plasmodium falciparum aspartic hemoglobinase. EMBO J. 13 (1994) 306–317. [PMID: 8313875]
3.  Gluzman, I.Y., Francis, S.E., Oksman, A., Smith, C.E., Duffin, K.L. and Goldberg, D.E. Order and specificity of the Plasmodium falciparum hemoglobin degradation pathway. J. Clin. Invest. 93 (1994) 1602–1608. [DOI] [PMID: 8163662]
[EC 3.4.23.38 created 1995]
 
 
EC 3.4.23.41     
Accepted name: yapsin 1
Reaction: Hydrolyses various precursor proteins with Arg or Lys in P1, and commonly Arg or Lys also in P2. The P3 amino acid is usually non-polar, but otherwise additional basic amino acids are favourable in both non-prime and prime positions
Other name(s): yeast aspartic protease 3; Yap3 gene product (Saccharomyces cerevisiae)
Comments: In peptidase family A1 of pepsin, and weakly inhibited by pepstatin. Can partially substitute for kexin in a deficient strain of yeast. The homologous product of the Mkc7 gene (Saccharomyces cerevisiae) has similar catalytic activity and has been termed yapsin 2 [2]
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, CAS registry number: 205132-58-7
References:
1.  Cawley, N.X., Chen, H.C., Beinfeld, M.C. and Loh, Y.P. Specificity and kinetic studies on the cleavage of various prohormone mono- and paired-basic residue sites by yeast aspartic protease 3. J. Biol. Chem. 271 (1996) 4168–4176. [DOI] [PMID: 8626758]
2.  Fuller, R.S. Yapsin 2. In: Barrett, A.J., Rawlings, N.D. and Woessner, J.F. (Eds), Handbook of Proteolytic Enzymes, Academic Press, London, 1998, pp. 908–909.
3.  Olsen, V., Guruprasad, K., Cawley, N.X., Chen, H.C., Blundell, T.L. and Loh, Y.P. Cleavage efficiency of the novel aspartic protease yapsin 1 (Yap3p) enhanced for substrates with arginine residues flanking the P1 site: correlation with electronegative active-site pockets predicted by molecular modeling. Biochemistry 37 (1998) 2768–2777. [DOI] [PMID: 9485427]
[EC 3.4.23.41 created 2000]
 
 
EC 3.4.23.43     
Accepted name: prepilin peptidase
Reaction: Typically cleaves a -Gly┼Phe- bond to release an N-terminal, basic peptide of 5-8 residues from type IV prepilin, and then N-methylates the new N-terminal amino group, the methyl donor being S-adenosyl-L-methionine
Comments: Many species of bacteria carry pili on their cell surfaces. These are virulence determinants in pathogenic strains, and are assembled biosynthetically from type IV prepilin subunits. Before assembly, the prepilin molecules require proteolytic processing, which is done by the prepilin peptidase. Prepilin peptidase and its homologues play a central role not only in type IV pilus biogenesis but also in transport of macromolecules across cell membranes. Although both peptide-bond hydrolysis and N-methylation are catalysed by the same molecule, the methylation can be inhibited without affecting peptidase activity, and it is believed that the enzyme has two separate catalytic sites. Type example of peptidase family A24.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, CAS registry number: 202833-59-8
References:
1.  Lory, S. and Strom, M.S. Structure-function relationship of type-IV prepilin peptidase of Pseudomonas aeruginosa - A review. Gene 192 (1997) 117–121. [DOI] [PMID: 9224881]
2.  LaPointe, C.F. and Taylor, R.K. The type 4 prepilin peptidases comprise a novel family of aspartic acid proteases. J. Biol. Chem. 275 (2000) 1502–1510. [DOI] [PMID: 10625704]
[EC 3.4.23.43 created 2001]
 
 
EC 3.4.23.45     
Accepted name: memapsin 1
Reaction: Broad endopeptidase specificity. Cleaves Glu-Val-Asn-Leu┼Asp-Ala-Glu-Phe in the Swedish variant of Alzheimer's amyloid precursor protein
Other name(s): β-secretase; β-site Alzheimer's amyloid precursor protein cleaving enzyme 2 (BACE2); ASP1; Down region aspartic protease
Comments: Can cleave β-amyloid precursor protein to form the amyloidogenic β-peptide that is implicated in the pathology of Alzheimer's disease, but is not significantly expressed in human brain. In peptidase family A1, but is atypical in containing a C-terminal membrane-spanning domain.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, SWISSPROT, CAS registry number: 447457-31-0
References:
1.  Turner, R.T., Loy, J.A., Nguyen, C., Devasamudram, T., Ghosh, A.K., Koelsch, G. and Tang, J. Specificity of memapsin 1 and its implications on the design of memapsin 2 (β-secretase) inhibitor selectivity. Biochemistry 41 (2002) 8742–8746. [DOI] [PMID: 12093293]
[EC 3.4.23.45 created 2003]
 
 
EC 3.4.23.47     
Accepted name: HIV-2 retropepsin
Reaction: Endopeptidase for which the P1 residue is preferably hydrophobic
Comments: In peptidase family A2. Responsible for the post-translational processing of the human immunodeficiency virus polyprotein.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, SWISSPROT, CAS registry number: 144114-21-6
References:
1.  Tözsér, J., Bláha, I., Copeland, T.D., Wondrak, E.M. and Oroszlan, S. Comparison of the HIV-1 and HIV-2 proteinases using oligopeptide substrates representing cleavage sites in Gag and Gag-Pol polyproteins. FEBS Lett. 281 (1991) 77–80. [DOI] [PMID: 2015912]
2.  Chen, Z., Li, Y., Chen, E., Hall, D., Darke, P., Culberson, C., Shafer, J.A. and Kuo, L.A. Crystal structure at 1.9-Å resolution of human immunodeficiency virus (HIV) II protease complexed with L-735,524, an orally bioavailable inhibitor of the HIV proteases. J. Biol. Chem. 269 (1994) 26344–26348. [PMID: 7929352]
[EC 3.4.23.47 created 2003]
 
 
EC 3.4.23.48     
Accepted name: plasminogen activator Pla
Reaction: Converts human Glu-plasminogen to plasmin by cleaving the Arg560┼Val peptide bond that is also hydrolysed by the mammalian u-plasminogen activator and t-plasminogen activator. Also cleaves arginyl bonds in other proteins
Comments: In peptidase family A26. From the bacterium Yersinia pestis that causes plague.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, SWISSPROT, CAS registry number: 101028-08-4
References:
1.  Kukkonen, M., Lähteenmäki, K., Suomalainen, M., Kalkkinen, N., Emödy, L., Laang, H. and Korhonen, T.K. Protein regions important for plasminogen activation and inactivation of α2-antiplasmin in the surface protease Pla of Yersinia pestis. Mol. Microbiol. 40 (2001) 1097–1111. [DOI] [PMID: 11401715]
[EC 3.4.23.48 created 2003]
 
 
EC 3.4.23.49     
Accepted name: omptin
Reaction: Has a virtual requirement for Arg in the P1 position and a slightly less stringent preference for this residue in the P1′ position, which can also contain Lys, Gly or Val.
Other name(s): protease VII; protease A; gene ompT proteins; ompT protease; protein a; Pla; OmpT
Comments: A product of the ompT gene of Escherichia coli, and associated with the outer membrane. Omptin shows a preference for cleavage between consecutive basic amino acids, but is capable of cleavage when P1′ is a non-basic residue [5,7]. Belongs in peptidase family A26.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, PDB, CAS registry number: 150770-86-8
References:
1.  Grodberg, J., Lundrigan, M.D., Toledo, D.L., Mangel, W.F. and Dunn, J.J. Complete nucleotide sequence and deduced amino acid sequence of the ompT gene of Escherichia coli K-12. Nucleic Acids Res. 16 (1988) 1209. [DOI] [PMID: 3278297]
2.  Sugimura, K. and Nishihara, T. Purification, characterization, and primary structure of Escherichia coli protease VII with specificity for paired basic residues: identity of protease VII and ompT. J. Bacteriol. 170 (1988) 5625–5632. [DOI] [PMID: 3056908]
3.  Hanke, C., Hess, J., Schumacher, G. and Goebel, W. Processing by OmpT of fusion proteins carrying the HlyA transport signal during secretion by the Escherichia coli hemolysin transport system. Mol. Gen. Genet. 233 (1992) 42–48. [PMID: 1603076]
4.  Dekker, N. Omptin. In: Barrett, A.J., Rawlings, N.D. and Woessner, J.F. (Eds), Handbook of Proteolytic Enzymes, 2nd edn, Elsevier, London, 2004, pp. 212–216.
5.  Vandeputte-Rutten, L., Kramer, R.A., Kroon, J., Dekker, N., Egmond, M.R. and Gros, P. Crystal structure of the outer membrane protease OmpT from Escherichia coli suggests a novel catalytic site. EMBO J. 20 (2001) 5033–5039. [DOI] [PMID: 11566868]
6.  Kramer, R.A., Vandeputte-Rutten, L., de Roon, G.J., Gros, P., Dekker, N. and Egmond, M.R. Identification of essential acidic residues of outer membrane protease OmpT supports a novel active site. FEBS Lett. 505 (2001) 426–430. [DOI] [PMID: 11576541]
7.  McCarter, J.D., Stephens, D., Shoemaker, K., Rosenberg, S., Kirsch, J.F. and Georgiou, G. Substrate specificity of the Escherichia coli outer membrane protease OmpT. J. Bacteriol. 186 (2004) 5919–5925. [DOI] [PMID: 15317797]
[EC 3.4.23.49 created 1993 as EC 3.4.21.87, transferred 2006 to EC 3.4.23.49]
 
 
EC 3.4.23.50     
Accepted name: human endogenous retrovirus K endopeptidase
Reaction: Processing at the authentic HIV-1 PR recognition site and release of the mature p17 matrix and the p24 capsid protein, as a result of the cleavage of the -SQNY┼PIVQ- cleavage site.
Other name(s): human endogenous retrovirus K10 endopeptidase; endogenous retrovirus HERV-K10 putative protease; human endogenous retrovirus K retropepsin; HERV K10 endopeptidase; HERV K10 retropepsin; HERV-K PR; HERV-K protease; HERV-K113 protease; human endogenous retrovirus K113 protease; human retrovirus K10 retropepsin
Comments: In peptidase family A2.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS
References:
1.  Towler, E.M., Gulnik, S.V., Bhat, T.N., Xie, D., Gustschina, E., Sumpter, T.R., Robertson, N., Jones, C., Sauter, M., Mueller-Lantzsch, N., Debouck, C. and Erickson, J.W. Functional characterization of the protease of human endogenous retrovirus, K10: can it complement HIV-1 protease. Biochemistry 37 (1998) 17137–17144. [DOI] [PMID: 9860826]
[EC 3.4.23.50 created 2009]
 
 
EC 3.4.23.52     
Accepted name: preflagellin peptidase
Reaction: Cleaves the signal peptide of 3 to 12 amino acids from the N-terminal of preflagellin, usually at Arg-Gly┼ or Lys-Gly┼, to release flagellin.
Other name(s): FlaK
Comments: An aspartic peptidase from Archaea but not bacteria. In peptidase family A24 (type IV prepilin peptidase family).
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc
References:
1.  Bardy, S.L. and Jarrell, K.F. FlaK of the archaeon Methanococcus maripaludis possesses preflagellin peptidase activity. FEMS Microbiol. Lett. 208 (2002) 53–59. [DOI] [PMID: 11934494]
2.  Ng, S.Y., VanDyke, D.J., Chaban, B., Wu, J., Nosaka, Y., Aizawa, S. and Jarrell, K.F. Different minimal signal peptide lengths recognized by the archaeal prepilin-like peptidases FlaK and PibD. J. Bacteriol. 191 (2009) 6732–6740. [DOI] [PMID: 19717585]
3.  Hu, J., Xue, Y., Lee, S. and Ha, Y. The crystal structure of GXGD membrane protease FlaK. Nature 475 (2011) 528–531. [DOI] [PMID: 21765428]
[EC 3.4.23.52 created 2011]
 
 
EC 3.4.24.3     
Accepted name: microbial collagenase
Reaction: Digestion of native collagen in the triple helical region at ┼Gly bonds. With synthetic peptides, a preference is shown for Gly at P3 and P1′, Pro and Ala at P2 and P2′, and hydroxyproline, Ala or Arg at P3′
Other name(s): Clostridium histolyticum collagenase; clostridiopeptidase A; collagenase A; collagenase I; Achromobacter iophagus collagenase; collagenase; aspergillopeptidase C; nucleolysin; azocollase; metallocollagenase; soycollagestin; Clostridium histolyticum proteinase A; clostridiopeptidase II; MMP-8; clostridiopeptidase I; collagen peptidase; collagen protease; collagenase MMP-1; metalloproteinase-1; kollaza; matrix metalloproteinase-1; MMP-1; matrix metalloproteinase-8; matirx metalloproteinase-18; interstitial collagenase
Comments: Six species of metalloendopeptidase acting on native collagen can be isolated from the medium of Clostridium histolyticum. Class I has forms α (68 kDa), β (115 kDa) and γ (79 kDa); class II has δ (100 kDa), ε (110 kDa) and ζ (125 kDa). The two classes are immunologically crossreactive, but have significantly different sequences, and different specificities such that their actions on collagen are complementary. The enzymes also act as peptidyl-tripeptidases. Variants of the enzyme have been purified from Bacillus cereus [10], Empedobacter collagenolyticum [4], Pseudomonas marinoglutinosa [1], and species of Vibrio, Vibrio B-30 (ATCC 21250) [2] and V. alginolyticus (previously Achromobacter iophagus) [3,8]. Also known from Streptomyces sp. [9]. The Vibrio enzyme is the type example of peptidase family M9.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, CAS registry number: 9001-12-1
References:
1.  Hanada, K., Mizutani, T., Yamagishi, M., Tsuji, H., Misaki, T. Sawada, J. The isolation of collagenase and its enzymological and physico-chemical properties. Agric. Biol. Chem. 37 (1973) 1771–1781.
2.  Merkel, J.R. and Dreisbach, J.H. Purification and characterization of a marine bacterial collagenase. Biochemistry 17 (1978) 2857–2863. [PMID: 210785]
3.  Heindl, M.-C., Fermandjian, S. and Keil, B. Circular dichroism comparative studies of two bacterial collagenases and thermolysin. Biochim. Biophys. Acta 624 (1980) 51–59. [DOI] [PMID: 6250633]
4.  Labadie, J. and Montel, M..-C. Purification et étude de quelques propriétés d’une collagénase produite par Empedobacter collagenolyticum. Biochimie 64 (1982) 49–54. [PMID: 6530724]
5.  Bond, M.D and Van Wart, H.D. Characterization of the individual collagenases from Clostridium histolyticum. Biochemistry 23 (1984) 3085–3091. [PMID: 6087888]
6.  Bond, M.D. and Van Wart, H.D. Relationship between the individual collagenases of Clostridium histolyticum: evidience for evolution by gene duplication. Biochemistry 23 (1984) 3092–3099. [PMID: 6087889]
7.  Van Wart, H.D. and Steinbrink, D.R. Complementary substrate specificities of class I and class II collagenases from Clostridium histolyticum. Biochemistry 24 (1985) 6520–6526. [PMID: 3002445]
8.  Tong, N.T., Tsugita, A. and Keil-Dlouha, V. Purification and characterization of two high-molecular-mass forms of Achromobacter collagenase. Biochim. Biophys. Acta 874 (1986) 296–304.
9.  Endo, A., Murakawa, S., Shimizu, H. and Shiraishi, Y. Purification and properties of collagenase from a Streptomyces species. J. Biochem. (Tokyo) 102 (1987) 163–170. [PMID: 2822678]
10.  Makinen, K.K. and Makinen, P.-L. Purification and properties of an extracellular collagenolytic protease produced by the human oral bacterium Bacillus cereus (strain Soc 67). J. Biol. Chem. 262 (1987) 12488–12495. [PMID: 3040751]
[EC 3.4.24.3 created 1961 as EC 3.4.4.19, transferred 1972 to EC 3.4.24.3 (EC 3.4.24.8 created 1978, incorporated 1992, EC 3.4.99.5 created 1972, incorporated 1978)]
 
 
EC 3.4.24.6     
Accepted name: leucolysin
Reaction: Cleavage of Phe1┼Val, His5┼Leu, Ala14┼Leu, Gly20┼Glu, Gly23┼Phe and Phe24┼Phe bonds in insulin B chain as well as N-blocked dipeptides
Other name(s): Leucostoma neutral proteinase; Leucostoma peptidase A
Comments: From the venom of the western cottonmouth moccasin snake (Agkistrodon piscivorus leucostoma).
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, CAS registry number: 72561-03-6
References:
1.  Wagner, F.W., Spiekerman, A.M. and Prescott, J.M. Leucostoma peptidase A. Isolation and physical properties. J. Biol. Chem. 243 (1968) 4486–4493. [PMID: 5684005]
2.  Spiekerman, A.M., Fredericks, K.K., Wagner, F.W. and Prescott, J.M. Leucostoma peptidase A: a metalloprotease from snake venom. Biochim. Biophys. Acta 293 (1973) 464–475. [DOI] [PMID: 4711816]
[EC 3.4.24.6 created 1978]
 
 
EC 3.4.24.13     
Accepted name: IgA-specific metalloendopeptidase
Reaction: Cleavage of Pro┼Thr bond in the hinge region of the heavy chain of human IgA
Other name(s): immunoglobulin A1 proteinase; IgA protease; IgA1-specific proteinase; IgA1 protease; IgA1 proteinase
Comments: A 190 kDa enzyme found in several pathogenic species of Streptococcus such as sanguis and pneumoniae. Type example of peptidase family M26. There is also an IgA-specific prolyl endopeptidase of the serine-type (see EC 3.4.21.72, IgA-specific serine endopeptidase)
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, CAS registry number: 72231-73-3
References:
1.  Kornfeld, S.J. and Plaut, A.G. Secretory immunity and the bacterial IgA proteases. Rev. Infect. Dis. 3 (1981) 521–534. [PMID: 6792682]
2.  Gilbert, J.V., Plaut, A.G. and Wright, A. Analysis of the immunoglobulin A protease gene of Streptococcus sanguis. Infect. Immun. 59 (1991) 7–17. [PMID: 1987065]
3.  Gilbert, J.V., Plaut, A.G., Fishman, Y. and Wright, A. Cloning of the gene encoding streptococcal immunoglobulin A protease and its expression in Escherichia coli. Infect. Immun. 56 (1988) 1961–1966. [PMID: 3294181]
[EC 3.4.24.13 created 1984]
 
 
EC 3.4.24.14     
Accepted name: procollagen N-endopeptidase
Reaction: Cleaves the N-propeptide of collagen chain α1(I) at Pro┼Gln and of α1(II) and α2(I) at Ala┼Gln
Other name(s): procollagen N-terminal peptidase; procollagen aminopeptidase; aminoprocollagen peptidase; aminoterminal procollagen peptidase; procollagen aminoterminal protease; procollagen N-terminal proteinase; type I/II procollagen N-proteinase; type III procollagen
Comments: Removes the propeptides of type I and II collagens prior to fibril assembly. Does not act on type III collagen. In peptidase family M12 (astacin family)
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, CAS registry number: 68651-94-5
References:
1.  Kohn, L.D., Iserky, C., Zupnik, J., Lenaers, A., Lee, G. and Lapiére, C.M. Calf tendon procollagen peptidase: its purification and endopeptidase mode of action. Proc. Natl. Acad. Sci. USA 71 (1974) 40–44. [DOI] [PMID: 4204204]
2.  Hojima, Y., McKenzie, J., van der Rest, M. and Prockop, D.J. Type I procollagen N-proteinase from chick embryo tendons. Purification of a new 500-kDa form of the enzyme and identification of the catalytically active polypeptides. J. Biol. Chem. 264 (1989) 11336–11345. [PMID: 2500439]
[EC 3.4.24.14 created 1984]
 
 
EC 3.4.24.20     
Accepted name: peptidyl-Lys metalloendopeptidase
Reaction: Preferential cleavage in proteins: -Xaa┼Lys- (in which Xaa may be Pro)
Other name(s): Armillaria mellea neutral proteinase; peptidyllysine metalloproteinase
Comments: From the honey fungus Armillaria mellea. In peptidase family M35 (deuterolysin family).
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 65979-41-1
References:
1.  Doonan S, Doonan HJ, Hanford R, Vernon CA, Walker JM, da Airold LP, Bossa F, Barra D, Carloni M, Fasella P, Riva F. The primary structure of aspartate aminotransferase from pig heart muscle. Digestion with a proteinase having specificity for lysine residues. Biochem. J. 149 (1975) 497–506. [PMID: 1239277]
2.  Lewis, W.G., Basford, J.M. and Walton, P.L. Specificity and inhibition studies of Armillaria mellea protease. Biochim. Biophys. Acta 522 (1978) 551–560. [DOI] [PMID: 23849]
[EC 3.4.24.20 created 1978 as EC 3.4.99.32, transferred 1992 to EC 3.4.24.20 (EC 3.4.99.30 created 1978, incorporated 1992)]
 
 
EC 3.4.24.21     
Accepted name: astacin
Reaction: Hydrolysis of peptide bonds in substrates containing five or more amino acids, preferentially with Ala in P1′, and Pro in P2′
Other name(s): Astacus proteinase; crayfish small-molecule proteinase
Comments: A 22.6 kDa digestive endopeptidase from the cardia of the crayfish Astacus fluviatilis. Type example of peptidase family M12.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 143179-21-9
References:
1.  Krauhs, E., Dörsam, H., Little, M., Zwilling, R. and Ponstingl, H. A protease from Astacus fluviatilis as an aid in protein sequencing. Anal. Biochem. 119 (1982) 153–157. [DOI] [PMID: 7041692]
2.  Titani, K., Torff, H.-J., Hormel, S., Kumar, S., Walsh, K.A., Rödl, J., Neurath, H. and Zwilling, R. Amino acid sequence of a unique protease from the crayfish Astacus fluviatilis. Biochemistry 26 (1987) 222–226. [PMID: 3548817]
3.  Stöcker, W., Wolz, R.L., Zwilling, R., Strydom, D.J. and Auld, D.S. Astacus protease, a zinc metalloenzyme. Biochemistry 27 (1988) 5026–5032.
4.  Stöcker, W., Ng, M. and Auld, D.S. Fluorescent oligopeptide substrates for kinetic characterization of the specificity of Astacus protease. Biochemistry 29 (1990) 10418–10425. [PMID: 2261483]
[EC 3.4.24.21 created 1972 as EC 3.4.99.6, transferred 1992 to EC 3.4.24.21]
 
 
EC 3.4.24.24     
Accepted name: gelatinase A
Reaction: Cleavage of gelatin type I and collagen types IV, V, VII, X. Cleaves the collagen-like sequence Pro-Gln-Gly┼Ile-Ala-Gly-Gln
Other name(s): 72-kDa gelatinase; matrix metalloproteinase 2; type IV collagenase (ambiguous); 3/4 collagenase (obsolete); matrix metalloproteinase 5 (obsolete); 72 kDa gelatinase type A; collagenase IV (ambiguous); collagenase type IV (ambiguous); MMP 2; type IV collagen metalloproteinase (ambiguous); type IV collagenase/gelatinase (ambiguous)
Comments: A secreted endopeptidase in peptidase family M10 (interstitial collagenase family), but possessing an additional fibronectin-like domain
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 146480-35-5
References:
1.  Murphy, G., McAlpine, C.G., Poll, C.T. and Reynolds, J.J. Purification and characterization of a bone metalloproteinase that degrades gelatin and types IV and V collagen. Biochim. Biophys. Acta 831 (1985) 49–58. [DOI] [PMID: 2994741]
2.  Collier, I.E., Wilhelm, S.M., Eisen, A.Z., Marmer, B.L., Grant, G.A., Seltzer, J.L., Kronberger, A., He, C., Bauer, E.A. and Goldberg, G.I. H-ras oncogene-transformed human bronchial epithelial cells (TBE-1) secrete a single metalloprotease capable of degrading basement membrane collagen. J. Biol. Chem. 263 (1988) 6579–6587. [PMID: 2834383]
3.  Okada, Y., Morodomi, T., Enghild, J.J., Suzuki, K., Yasui, A., Nakanishi, I., Salvesen, G. and Nagase, H. Matrix metalloproteinase 2 from human rheumatoid synovial fibroblasts-purification and activation of the precursor and enzymic properties. Eur. J. Biochem. 194 (1990) 721–730. [DOI] [PMID: 2269296]
[EC 3.4.24.24 created 1992]
 
 
EC 3.4.24.25     
Accepted name: vibriolysin
Reaction: Preferential cleavage of bonds with bulky hydrophobic groups in P2 and P1′. Phe at P1′ is the most favoured residue, which distinguished this enzyme from thermolysin
Other name(s): Aeromonas proteolytica neutral proteinase; aeromonolysin
Comments: Thermostable enzyme from Vibrio proteolyticus (formerly Aeromonas proteolytica). Specificity related to, but distinct from, those of thermolysin and bacillolysin [1]. A zinc metallopeptidase in family M4 (thermolysin family). Formerly included in EC 3.4.24.4
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, CAS registry number: 69598-88-5
References:
1.  Holmquist, B. and Vallee, B.L. Esterase activity of zinc neutral proteases. Biochemistry 15 (1976) 101–107. [PMID: 2276]
2.  Wilkes, S.H. and Prescott, J.M. Aeromonas neutral protease. Methods Enzymol. 45 (1976) 404–415. [DOI] [PMID: 1012006]
3.  Bayliss, M.E., Wilkes, S.H. and Prescott, J.M. Aeromonas neutral protease: specificity toward extended substrates. Arch. Biochem. Biophys. 204 (1980) 214–219. [DOI] [PMID: 7000005]
4.  Wilkes, S.H., Bayliss, M.E. and Prescott, J.M. Critical ionizing groups in Aeromonas neutral protease. J. Biol. Chem. 263 (1988) 1821–1825. [PMID: 3123480]
5.  David, V.A., Deutch, A.H., Sloma, A., Pawlyk, D., Ally, A. and Durham, D.R. Cloning, sequencing and expression of the gene encoding the extracellular neutral protease, vibriolysin, of Vibrio proteolyticus. Gene 112 (1992) 107–112. [DOI] [PMID: 1551587]
[EC 3.4.24.25 created 1972 as EC 3.4.24.4, part transferred 1992 to EC 3.4.24.25, modified 1997]
 
 
EC 3.4.24.26     
Accepted name: pseudolysin
Reaction: Hydrolysis of proteins including elastin, collagen types III and IV, fibronectin and immunoglobulin A, generally with bulky hydrophobic group at P1′. Insulin B chain cleavage pattern identical to that of thermolysin, but specificity differs in other respects
Other name(s): Pseudomonas elastase; Pseudomonas aeruginosa neutral metalloproteinase
Comments: In peptidase family M4 (thermolysin family). From the pathogenic bacteria Pseudomonas aeruginosa and Legionella pneumophila, and causes tissue damage.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 171715-23-4
References:
1.  Morihara, K. and Tsuzuki, H. Pseudomonas aeruginosa elastase: affinity chromatography and some properties as a metallo-neutral proteinase. Agric. Biol. Chem. 39 (1975) 1123–1128.
2.  Nishino, N. and Powers, J.C. Pseudomonas aeruginosa elastase. Development of a new substrate, inhibitors, and an affinity ligand. J. Biol. Chem. 255 (1980) 3482–3486. [PMID: 6767718]
3.  Dreyfus, L.A. and Iglewski, B.H. Purification and characterization of an extracellular protease of Legionella pneumophila. Infect. Immun. 70 (1986) 736–743. [PMID: 3512431]
4.  Bever, R.A. and Iglewski, B.H. Molecular characterization and nucleotide sequence of the Pseudomonas aeruginosa elastase structural gene. J. Bacteriol. 170 (1988) 4309–4314. [DOI] [PMID: 2842313]
5.  Black, W.J., Quinn, F.D. and Tompkins, L.S. Legionella pneumophila zinc metalloprotease is structurally and functionally homologous to Pseudomonas aeruginosa elastase. J. Bacteriol. 172 (1990) 2608–2613. [DOI] [PMID: 2110146]
[EC 3.4.24.26 created 1972 as EC 3.4.24.4, part transferred 1992 to EC 3.4.24.26]
 
 
EC 3.4.24.27     
Accepted name: thermolysin
Reaction: Preferential cleavage: ┼Leu > ┼Phe
Other name(s): Bacillus thermoproteolyticus neutral proteinase; thermoase; thermoase Y10; TLN
Comments: A thermostable extracellular metalloendopeptidase containing four calcium ions. Enzymes that may be species variants of thermolysin are reported from Micrococcus caseolyticus [4] and Aspergillus oryzae [5]. Type example of peptidase family M4. Closely related but distinct enzymes are aeromonolysin, pseudolysin, bacillolysin, aureolysin and mycolysin
Links to other databases: BRENDA, EXPASY, GTD, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 9073-78-3
References:
1.  Ohta, Y. Ogura, Y. and Wada, A. Thermostable protease from thermophilic bacteria. I. Thermostability, physicochemical properties, and amino acid composition. J. Biol. Chem. 241 (1966) 5919–5925. [PMID: 5954368]
2.  Morihara, K., Tsuzuki, H. and Oka, T. Comparison of the specificities of various neutral proteinases from microorganisms. Arch. Biochem. Biophys. 123 (1968) 572–588. [DOI] [PMID: 4967801]
3.  Latt, S. A., Holmquist, B. and Vallee, B. L. Thermolysin: a zinc metalloenzyme. Biochem. Biophys. Res. Commun. 37 (1969) 333–339. [DOI] [PMID: 5823940]
4.  Desmazeaud, M. J. and Hermier, J. H. Spécificité de la protéase neutre de Micrococcus caseolyticus. Eur. J. Biochem. 19 (1971) 51–55. [DOI] [PMID: 5551628]
5.  Morihara, K. and Tsuzuki, H. Comparative study of various neutral proteinases from microorganisms: specificity with oligopeptides. Arch. Biochem. Biophys. 146 (1971) 291–296. [DOI] [PMID: 5004124]
6.  Titani, K., Hermodson, M. A., Ericson, L. H., Walsh, K. A. and Neurath, H. Amino-acid sequence of thermolysin. Nature New Biol. 238 (1972) 35–37. [PMID: 18663848]
7.  Matthews, B. W. Structural basis of the action of thermolysin and related zinc peptidases. Acc. Chem. Res. 21 (1988) 333–340.
[EC 3.4.24.27 created 1972 as EC 3.4.24.4, part transferred 1992 to EC 3.4.24.27]
 
 
EC 3.4.24.28     
Accepted name: bacillolysin
Reaction: Similar, but not identical, to that of thermolysin
Other name(s): Bacillus metalloendopeptidase; Bacillus subtilis neutral proteinase; anilozyme P 10; Bacillus metalloproteinase; Bacillus neutral proteinase; megateriopeptidase
Comments: Variants of this enzyme have been found in species of Bacillus including B. subtilis [1,6], B. amyloliquefaciens [5], B. megaterium (megateriopeptidase, [2]), B. mesentericus [10], B. cereus [3,8,9] and B. stearothermophilus [7]. In peptidase family M4 (thermolysin family). Formerly included in EC 3.4.24.4
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 9080-56-2
References:
1.  Morihara, K., Tsuzuki, H. and Oka, T. Comparison of the specificities of various neutral proteinases from microorganisms. Arch. Biochem. Biophys. 123 (1968) 572–588. [DOI] [PMID: 4967801]
2.  Millet, J. and Acher, R. Spécificité de la mégatériopeptidase: une amino-endopeptidase à caractère hydrophobe. Eur. J. Biochem. 9 (1969) 456–462. [DOI] [PMID: 4980359]
3.  Feder, J., Keay, L., Garrett, L.R., Cirulis, N., Moseley, M.H. and Wildi, B.S. Bacillus cereus neutral protease. Biochim. Biophys. Acta 251 (1971) 74–78. [DOI] [PMID: 5002444]
4.  Holmquist, B. and Vallee, B.L. Esterase activity of zinc neutral proteases. Biochemistry 15 (1976) 101–107. [PMID: 2276]
5.  Vasantha, N., Thompson, L.D., Rhodes, C., Banner, C., Nagle, J. and Filpula, D. Genes for alkaline protease and neutral protease from Bacillus amyloliquefaciens contain a large open reading frame between the regions coding for signal sequence and mature protein. J. Bacteriol. 159 (1984) 811–819. [PMID: 6090391]
6.  Yang, M.Y., Ferrari, E. and Henner, D.J. Cloning of the neutral protease gene of Bacillus subtilis and the use of the cloned gene to create an in vitro-derived deletion mutation. J. Bacteriol. 160 (1984) 15–21. [PMID: 6090407]
7.  Takagi, M., Imanaka, T. and Aiba, S. Nucleotide sequence and promoter region for the neutral protease gene from Bacillus stearothermophilus. J. Bacteriol. 163 (1985) 824–831. [PMID: 2993245]
8.  Sidler, W., Niederer, E., Suter, F. and Zuber, H. The primary structure of Bacillus cereus neutral proteinase and comparison with thermolysin and Bacillus subtilis neutral proteinase. Biol. Chem. Hoppe-Seyler 367 (1986) 643–657. [PMID: 3092843]
9.  Pauptit, R.A., Karlson, R., Picot, D., Jenkins, J.A., Niklaus-Reimer, A.-S. and Jansonius, J.N. Crystal structure of neutral protease from Bacillus cereus refined at 3.0 Å resolution and comparison with the homologous but more thermostable enzyme thermolysin. J. Mol. Biol. 199 (1988) 525–537. [DOI] [PMID: 3127592]
10.  Stoeva, S., Kleinschmidt, T., Mesrob, B. and Braunitzer, G. Primary structure of a zinc protease from Bacillus mesentericus strain 76. Biochemistry 29 (1990) 527–534. [PMID: 2302386]
[EC 3.4.24.28 created 1972 as EC 3.4.24.4, part transferred 1992 to EC 3.4.24.28]
 
 
EC 3.4.24.29     
Accepted name: aureolysin
Reaction: Cleavage of insulin B chain with specificity similar to that of thermolysin, preferring hydrophobic P1′ residue. Activates the glutamyl endopeptidase (EC 3.4.21.19) of Staphylococcus aureus
Other name(s): Staphylococcus aureus neutral proteinase; Staphylococcus aureus neutral protease
Comments: A metalloenzyme from S. aureus earlier confused with staphylokinase (a non-enzymic activator of plasminogen).
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 39335-13-2
References:
1.  Arvidson, S. Studies on extracellular proteolytic enzymes from Staphylococcus aureus. II. Isolation and characterization of an EDTA-sensitive protease. Biochim. Biophys. Acta 302 (1973) 149–157. [DOI] [PMID: 4632563]
2.  Saheb, S.A. Purification et caractérisation d’une protéase extracellulaire de Staphylococcus aureus inhibée par l’E.D.T.A. Biochimie 58 (1976) 793–804. [DOI] [PMID: 823980]
3.  Drapeau, G.R. Role of a metalloprotease in activation of the precursor of staphylococcal protease. J. Bacteriol. 136 (1978) 607–613. [PMID: 711676]
4.  Potempa, J., Porwit-Bohr, Z. and Travis, J. Stabilization vs. degradation of Staphylococcus aureus metalloproteinase. Biochim. Biophys. Acta 993 (1989) 301–304. [DOI] [PMID: 2512988]
[EC 3.4.24.29 created 1972 as EC 3.4.24.4, part transferred 1992 to EC 3.4.24.29]
 
 
EC 3.4.24.30     
Accepted name: coccolysin
Reaction: Preferential cleavage: ┼Leu, ┼Phe, ┼Tyr, ┼Ala
Other name(s): Streptococcus thermophilus intracellular proteinase; EM 19000
Comments: A 30 kDa endopeptidase found intracellularly in S. thermophilus [1] and S. diacetilactis [2] and in the medium of S. faecalis [3,4]. In peptidase family M4 (thermolysin family). Formerly included in EC 3.4.24.4
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, CAS registry number: 156859-08-4
References:
1.  Desmazeaud, M.J. Propriétés générales et spécificité d’action d’une endopeptidase neutre intracellulaire de Streptococcus thermophilus. Biochimie 56 (1974) 1173–1181. [DOI] [PMID: 4451671]
2.  Desmazeaud, M.J. and Zevaco, C. General properties and substrate specificity of an intracellular neutral protease from Streptococcus diacetilactis. Ann. Biol. Anim. Biochem. Biophys. 16 (1976) 851–868.
3.  Smith, R.A.G., Green, J. and Kopper, P.H. The purification and properties of a fibrinolytic neutral metalloendopeptidase from Streptococcus faecalis. Arch. Biochem. Biophys. 202 (1980) 629–638. [DOI] [PMID: 6779709]
4.  Mäkinen, P.-L., Clewell, D.B., An, F., Mäkinen, K.K. Purification and substrate specificity of a strongly hydrophobic extracellular metalloendopeptidase ("gelatinase") from Streptococcus faecalis (strain 0G1-10). J. Biol. Chem. 264 (1989) 3325–3334. [PMID: 2536744]
[EC 3.4.24.30 created 1972 as EC 3.4.24.4, part transferred 1992 to EC 3.4.24.30]
 
 
EC 3.4.24.31     
Accepted name: mycolysin
Reaction: Preferential cleavage of bonds with hydrophobic residues in P1′
Other name(s): pronase component; Streptomyces griseus neutral proteinase; actinase E; SGNPI
Comments: From Streptomyces griseus, S. naraensis, and S. cacaoi. Specificity similar to that of thermolysin, but much more sensitive to inhibition by mercaptoacetyl-Phe-Leu. Little structural similarity to other bacterial metalloendopeptidases. Type example of peptidase family M5. Formerly included in EC 3.4.24.4
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, CAS registry number: 153190-34-2
References:
1.  Morihara, K., Tsuzuki, H. and Oka, T. Comparison of the specificities of various neutral proteinases from microorganisms. Arch. Biochem. Biophys. 123 (1968) 572–588. [DOI] [PMID: 4967801]
2.  Hiramatsu, A. and Ouchi, T. A neutral proteinase from Streptomyces naraensis. J. Biochem. (Tokyo) 71 (1972) 767–781. [PMID: 5073323]
3.  Blumberg, S. and Tauber, Z. Inhibition of metalloendopeptidases by 2-mercaptoacetyl-dipeptides. Eur. J. Biochem. 136 (1983) 151–154. [DOI] [PMID: 6413206]
4.  Chang, P.C., Kue, T-C., Tsugita, A. and Lee, Y.H.W. Extracellular metalloprotease gene of Streptomyces cacaoi: structure, nucleotide sequence and characterization of the cloned gene product. Gene 88 (1990) 87–95. [DOI] [PMID: 2341042]
[EC 3.4.24.31 created 1972 as EC 3.4.24.4, part transferred 1992 to EC 3.4.24.31]
 
 
EC 3.4.24.32     
Accepted name: β-lytic metalloendopeptidase
Reaction: Cleavage of N-acetylmuramoyl┼Ala, and of the insulin B chain at Gly23┼Phe > Val18┼Cya
Other name(s): Myxobacter β-lytic proteinase; achromopeptidase component; β-lytic metalloproteinase; β-lytic protease; Myxobacterium sorangium β-lytic proteinase; Myxobacter495 β-lytic proteinase
Comments: From Achromobacter lyticus and Lysobacter enzymogenes. Digests bacterial cell walls. Type example of peptidase family M23.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, CAS registry number: 37288-92-9
References:
1.  Whitaker, D.R., Roy, C., Tsai, C.S. and Juraöek, L. Lytic enzymes of Sorangium sp. A comparison of the proteolytic properties of the α- and β-lytic proteases. Can. J. Biochem. 43 (1965) 1961–1970. [PMID: 5880182]
2.  Whitaker, D.R. and Roy, C. Concerning the nature of the α- and β-lytic proteases of Sorangium sp. Can. J. Biochem. 45 (1967) 911. [PMID: 6034704]
3.  Li, S. L., Norioka, S. and Sakiyama, F. Molecular cloning and nucleotide sequence of the β-lytic protease gene from Achromobacter lyticus. J. Bacteriol. 172 (1990) 6506–6511. [DOI] [PMID: 2228973]
[EC 3.4.24.32 created 1972 as EC 3.4.24.4, part transferred 1992 to EC 3.4.24.32]
 
 
EC 3.4.24.36     
Accepted name: leishmanolysin
Reaction: Preference for hydrophobic residues at P1 and P1′ and basic residues at P2′ and P3′. A model nonapeptide is cleaved at -Ala-Tyr┼Leu-Lys-Lys-
Other name(s): promastigote surface endopeptidase; glycoprotein gp63; Leishmania metalloproteinase; surface acid proteinase; promastigote surface protease
Comments: A membrane-bound glycoprotein found on the promastigote of various species of Leishmania protozoans. Contains consensus sequence for a zinc-binding site; Z-Tyr-Leu-NHOH is a strong inhibitor. The enzyme can activate its proenzyme by cleavage of the Val100┼Val bond. An acid pH optimum is found with certain protein substrates. Type example of peptidase family M8
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 161052-06-8
References:
1.  Button, L.L. and McMaster, W.R. Molecular cloning of the major surface antigen of Leishmania. J. Exp. Med. 167 (1988) 724–729. [PMID: 3346625]
2.  Bouvier, J., Cordier, C., Vogel, H., Reichelt, R. and Etges, R. Characterization of the promastigote surface protease of Leishmania as a membrane-bound zinc endopeptidase. Mol. Biochem. Parasitol. 37 (1989) 235–246. [DOI] [PMID: 2608099]
3.  Chaudhuri, G., Chaudhuri, M., Pan, A. and Chang, K.-P. Surface acid proteinase (gp63) of Leishmania mexicana. A metalloenzyme capable of protecting liposome-encapsulated proteins from phagolysosomal degradation by macrophages. J. Biol. Chem. 264 (1989) 7483–7489. [PMID: 2708373]
4.  Bouvier, J., Schneider, P., Etges, R. and Bordier, C. Peptide substrate specificity of the membrane-bound metalloprotease of Leishmania. Biochemistry 29 (1990) 10113–10119. [PMID: 2271643]
[EC 3.4.24.36 created 1992]
 
 
EC 3.4.24.38     
Accepted name: gametolysin
Reaction: Cleavage of the proline- and hydroxyproline-rich proteins of the Chlamydomonas cell wall; also cleaves azocasein, gelatin and Leu-Trp-Met┼Arg-Phe-Ala
Other name(s): autolysin, Chlamydomonas cell wall degrading protease; lysin; Chlamydomonas reinhardtii metalloproteinase; gamete lytic enzyme; gamete autolysin
Comments: A glycoprotein found in the periplasmic space of Chlamydomonas reinhardtii gametes in a 62 kDa inactive form; decreased to 60 kDa upon activation. A zinc enzyme, inhibited by phosphoramidon, but also thiol activated. Type example of peptidase family M11
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, CAS registry number: 97089-74-2
References:
1.  Jaenicke, L., Kunhe, W., Spessert, R., Wahle, U. and Waffenschmidt, S. Cell-wall lytic enzymes (autolysins) of Chlamydomonas reinhardtii are (hydroxy)proline-specific proteases. Eur. J. Biochem. 170 (1987) 485–491. [PMID: 3319620]
2.  Buchanan, M.J., Imam, S.H., Eskue, W.A. and Snell, W.J. Activation of the cell wall degrading protease, lysin, during sexual signalling in Chlamydomonas: the enzyme is stored as an inactive, higher relative molecular mass precursor in the periplasm. J. Cell. Biol. 108 (1989) 199–207. [PMID: 2910877]
3.  Matsuda, Y. Gametolysin. In: Barrett, A.J., Rawlings, N.D. & Woessner, J.F. (Eds), Handbook of Proteolytic Enzymes, Academic Press, London, 1998, pp. 1140–1143.
[EC 3.4.24.38 created 1992, modified 2000]
 
 
EC 3.4.24.39     
Accepted name: deuterolysin
Reaction: Preferential cleavage of bonds with hydrophobic residues in P1&prime
also Asn3┼Gln and Gly8┼Ser bonds in insulin B chain
Other name(s): Penicillium roqueforti protease II; microbial neutral proteinase II; acid metalloproteinase; neutral proteinase II; Penicillium roqueforti metalloproteinase
Comments: Proteolytic activity found in Penicillium roqueforti [4], P. caseicolum [4], Aspergillus sojae [3] and A. oryzae [1,5]. Optimum pH of 5 for digesting various proteins. Strong action on protamine and histones. Insensitive to phosphoramidon. About 20 kDa. A distinct Aspergillus sojae endopeptidase is larger and has a neutral pH optimum. Type example of peptidase family M35. Formerly included in EC 3.4.24.4
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 247028-11-1
References:
1.  Nakadai, T., Nasuno, S. and Iguchi, N. Purification and properties of neutral proteinase II from Aspergillus oryzae. Agric. Biol. Chem. 37 (1973) 2703–2708.
2.  Gripon, J.-C. and Hermier, J. Le système protéolytique de Penicillium roqueforti. III. Purification, propriétés et spécificité d’une protéase inhibée par l’E.D.T.A. Biochimie 56 (1974) 1324–1332. [PMID: 4219726]
3.  Sekine, H. , Neutral proteinases I and II of Aspergillus sojae action on various substrates. Agric. Biol. Chem. 40 (1976) 703–709.
4.  Gripon, J.C., Auberger, B. and Lenoir, J. Metalloproteases from Penicillium caseicolum and P. roqueforti: comparision of specificity and chemical characterization. Int. J. Biochem. 12 (1980) 451–455. [PMID: 6998789]
5.  Vaganova, T.I., Ivanova, N.M. and Stepanov, V.M. Isolation and properties of the "acid" metalloproteinase from Aspergillus oryzae. Biochemistry (Mosc) 53 (1988) 1171–1178.
[EC 3.4.24.39 created 1972 as EC 3.4.24.4, part transferred 1992 to EC 3.4.24.39]
 
 
EC 3.4.24.40     
Accepted name: serralysin
Reaction: Preferential cleavage of bonds with hydrophobic residues in P1′
Other name(s): Pseudomonas aeruginosa alkaline proteinase; Escherichia freundii proteinase; Serratia marcescens extracellular proteinase; Serratia marcescens metalloproteinase; Pseudomonas aeruginosa alk. protease; Serratia marcescens metalloprotease
Comments: A 50 kDa extracellular endopeptidase from Pseudomonas aeruginosa [1,2,6], Escherichia freundii [3], Serratia marcescens [4,5,6] and Erwinia chrysanthemi [7]. There is broad specificity in cleavage of the insulin B chain, with some species variations. The pH optimum for digesting various proteins is about 9 - 10. In peptidase family M10 (interstitial collagenase family). Formerly included in EC 3.4.24.4
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 70851-98-8
References:
1.  Morihara, K., Tsuzuki, H. and Oka, T. Comparison of the specificities of various neutral proteinases from microorganisms. Arch. Biochem. Biophys. 123 (1968) 572–588. [DOI] [PMID: 4967801]
2.  Morihara, K., Tsuzuki, H. and Oka, T. On the specificity of Pseudomonas aeruginosa alkaline proteinase with synthetic peptides. Biochim. Biophys. Acta 309 (1973) 414–429. [DOI] [PMID: 4199986]
3.  Nakajima, M., Mizusawa, K. and Yoshida, F. Purification and properties of an extracellular proteinase of psychrophilic Escherichia freundii. Eur. J. Biochem. 44 (1974) 87–96. [DOI] [PMID: 4212288]
4.  Decedue, C.J., Broussard, E.A., II, L arson, A.D. and Braymer, H.D. Purification and characterization of the extracellular proteinase of Serratia marcescens. Biochim. Biophys. Acta 569 (1979) 293–301. [DOI] [PMID: 383155]
5.  Doerr, M. and Traub, W.H. Purification and characterization of two Serratia marcescens proteases. Zentralbl. Bakteriol., Mikrobiol. Hyg. Ser. A 257 (1984) 6–19. [PMID: 6380155]
6.  Nakahama, K., Yoshimura, K., Marumoto, R., Kikuchi, M., Lee, I.S., Hase, T. and Matsubara, H. Cloning and sequencing of Serratia protease gene. Nucleic Acids Res. 14 (1986) 5843–5856. [DOI] [PMID: 3016665]
7.  Dahler, G.S., Barras, F. and Keen, N.T. Cloning of genes encoding extracellular metalloproteases from Erwinia chrysanthemi EC16. J. Bacteriol. 172 (1990) 5803–5815. [DOI] [PMID: 2211513]
8.  Okuda, K., Morihara, K., Atsumi, Y., Takeuchi, H., Kawamoto, S., Kawasaki, H., Suzuki, K. and Fukushima, J. Complete nucleotide sequence of the structural gene for alkaline proteinase from Pseudomonas aeruginosa IFO 3455. Infect. Immun. 58 (1990) 4083–4088. [PMID: 2123832]
[EC 3.4.24.40 created 1972 as EC 3.4.24.4, part transferred 1992 to EC 3.4.24.40]
 
 
EC 3.4.24.42     
Accepted name: atrolysin C
Reaction: Cleavage of His5┼Leu, His10┼Leu, Ala14┼Leu, Tyr16┼Leu and Gly23┼Phe bonds in B chain of insulin. With small molecule substrates prefers hydrophobic residue at P2′ and small residue such as Ala, Gly at P1
Other name(s): Crotalus atrox metalloendopeptidase c; hemorrhagic toxin c and d
Comments: A 24 kDa hemorrhagic endopeptidase from the venom of the western diamondback rattlesnake (Crotalus atrox) that digests type IV collagen, and exists as two forms, c and d. Phosphoramidon inhibits in the 0.1 mM range. In peptidase family M12 (astacin family). Hemorrhagic toxin-2 of C. ruber ruber has the same Mr and specificity and is a homologue [4,6].
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 158886-17-0
References:
1.  Bjarnason, J.B. and Tu, A.T. Hemorrhagic toxins from western diamondback rattlesnake (Crotalus atrox) venom: isolation and characterization of five toxins and the role of zinc in hemorrhagic toxin e. Biochemistry 17 (1978) 3395–3404. [PMID: 210790]
2.  Fox, J.W., Campbell, R., Beggerly, L. and Bjarnason, J.B. Substrate specificities and inhibition of two hemorrhagic zinc proteases Ht-c and Ht-d from Crotalus atrox venom. Eur. J. Biochem. 156 (1986) 65–72. [DOI] [PMID: 3514216]
3.  Bjarnason, J.B. and Fox, J.W. Characterization of two hemorrhagic zinc proteinases, toxin c and toxin d, from western diamondback rattlesnake (Crotalus atrox) venom. Biochim. Biophys. Acta 911 (1987) 356–363. [DOI] [PMID: 3101740]
4.  Mori, N., Nikai, T., Sugihara, H. and Tu, A.T. Biochemical characterization of hemorrhagic toxins with fibrinogenase activity isolated from Crotalus ruber ruber venom. Arch. Biochem. Biophys. 253 (1987) 108–121. [DOI] [PMID: 2949699]
5.  Shannon, J.D., Baramova, E.N., Bjarnason, J.B. and Fox, F.W. Amino acid sequence of a Crotalus atrox venom metalloproteinase which cleaves type IV collagen and gelatin. J. Biol. Chem. 264 (1989) 11575–11583. [PMID: 2745407]
6.  Takeya, H., Onikura, A., Nikai, T., Sugihara, H. and Iwanaga, S. Primary structure of a hemorrhagic metalloproteinase, HT- 2, isolated from the venom of Crotalus ruber ruber. J. Biochem. (Tokyo) 108 (1990) 711–719. [PMID: 2081731]
[EC 3.4.24.42 created 1992]
 
 
EC 3.4.24.43     
Accepted name: atroxase
Reaction: Cleavage of His5┼Leu, Ser9┼His, His10┼Leu, Ala14┼Leu and Tyr16┼Leu of insulin B chain
Comments: A nonhemorrhagic endopeptidase from the venom of the western diamondback rattlesnake (Crotalus atrox) that cleaves fibrinogen. In peptidase family M12 (astacin family)
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, CAS registry number: 181186-94-7
References:
1.  Willis, T.W. and Tu, A.T. Purification and biochemical characterization of atroxase, a nonhemorrhagic fibrinolytic protease from western diamondback rattlesnake venom. Biochemistry 27 (1988) 4769–4777. [PMID: 3167016]
[EC 3.4.24.43 created 1992]
 
 
EC 3.4.24.44     
Accepted name: atrolysin E
Reaction: Cleavage of Asn3┼Gln, Ser9┼His and Ala14┼Leu bonds in insulin B chain and Tyr14┼Gln and Thr8┼Ser in A chain. Cleaves type IV collagen at Ala73┼Gln in α1(IV) and at Gly7┼Leu in α2(IV)
Other name(s): Crotalus atrox metalloendopeptidase e; hemorrhagic toxin e
Comments: A 25.7 kDa hemorrhagic endopeptidase from the venom of the western diamondback rattlesnake (Crotalus atrox) that digests basement membrane components, including the triple helix of type IV collagen. Such action is believed to contribute to the hemorrhagic property by weakening capillary walls. In peptidase family M12 (astacin family)
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, CAS registry number: 172306-51-3
References:
1.  Bjarnason, J.B. and Tu, A.T. Hemorrhagic toxins from western diamondback rattlesnake (Crotalus atrox) venom: isolation and characterization of five toxins and the role of zinc in hemorrhagic toxin e. Biochemistry 17 (1978) 3395–3404. [PMID: 210790]
2.  Bjarnason, J.B. and Fox, J.W. Proteolytic specificity and cobalt exchange of hemorrhagic toxin e, a zinc protease isolated from the venom of the western diamondback rattlesnake (Crotalus atrox). Biochemistry 22 (1983) 3770–3778. [PMID: 6351911]
3.  Baramova, E.N., Shannon, J.D., Bjarnason, J.B. and Fox, J.W. Identification of the cleavave sites by a hemorrhagic metalloproteinase in type IV collagen. Matrix 10 (1990) 91–97. [PMID: 2374521]
[EC 3.4.24.44 created 1992]
 
 
EC 3.4.24.50     
Accepted name: bothrolysin
Reaction: Cleavage of Gln4┼His, Ser9┼His and Ala14┼Leu of insulin B chain and Pro┼Phe of angiotensin I
Other name(s): Bothrops metalloendopeptidase J; J protease
Comments: A 22.5 kDa endopeptidase from the venom of the jararaca snake (Bothrops jararaca), insensitive to phosphoramidon at 0.5 mM. In peptidase family M12 (astacin family)
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, CAS registry number: 443890-65-1
References:
1.  Tanizaki, M.M., Zingali, R.B., Kawazaki, H., Imajoh, S., Yamazaki, S. and Suzuki, K. Purification and some characteristics of a zinc metalloprotease from the venom of Bothrops jararaca (jararaca). Toxicon 27 (1989) 747–755. [PMID: 2781574]
[EC 3.4.24.50 created 1992]
 
 
EC 3.4.24.51     
Accepted name: ophiolysin
Reaction: Cleavage of Asn3┼Gln, Gln4┼His, His10┼Leu, Ala14┼Leu, and Tyr16┼Leu in insulin B chain
Other name(s): Ophiophagus metalloendopeptidase
Comments: A 70 kDa endopeptidase from the venom of the king cobra (Ophiophagus hannah)
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc
References:
1.  Yamakawa, Y. and Omori-Satoh, T. A protease in the venom of king cobra (Ophiophagus hannah): purification, characterization and substrate specificity on oxidized insulin B-chain. Toxicon 26 (1988) 1145–1155. [PMID: 3070833]
[EC 3.4.24.51 created 1992]
 
 
EC 3.4.24.52     
Accepted name: trimerelysin I
Reaction: Cleavage of only two bonds His10┼Leu and Ala14┼Leu in the insulin B chain
Other name(s): Trimeresurus metalloendopeptidase I; hemorrhagic proteinase HR1A; hemorrhagic metalloproteinase HR1A; metalloproteinase HR1A
Comments: A 60 kDa hemorrhagic endopeptidase of pI 4.4 from the venom of the habu snake (Trimeresurus flavoviridis). In peptidase family M12 (astacin family)
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, CAS registry number: 151125-16-5
References:
1.  Omori-Satoh, T. and Sadahiro, S. Resolution of the major hemorrhagic component of Trimeresurus flavoviridis venom into two parts. Biochim. Biophys. Acta 580 (1979) 392–404. [DOI] [PMID: 518906]
2.  Yamakawa, Y. and Omori-Satoh, T. The sites of cleavage in oxidized insulin-B chain by a hemorrhagic protease derived from the venom of the habu (Trimeresurus flavoviridis). Toxicon 26 (1988) 227–231. [PMID: 3284004]
3.  Takeya, H., Oda, K., Miyata, T., Omori-Satoh, T. and Iwanaga, S. The complete amino acid sequence of the high molecular mass hemorrhagic protein HR1B isolated from the venom of Trimeresurus flavoviridis. J. Biol. Chem. 265 (1990) 16068–16073. [PMID: 2398046]
[EC 3.4.24.52 created 1992]
 
 
EC 3.4.24.55     
Accepted name: pitrilysin
Reaction: Preferential cleavage of -Tyr16┼ Leu- and -Phe25┼ Tyr-bonds of oxidized insulin B chain. Also acts on other substrates of less than 7 kDa such as insulin and glucagon
Other name(s): Escherichia coli protease III; protease Pi; proteinase Pi; PTR; Escherichia coli metalloproteinase Pi
Comments: From the periplasmic space of Escherichia coli. Inhibited by EDTA and 1,10-phenanthroline; not thiol-dependent. Type example of peptidase family M16
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 81611-78-1
References:
1.  Finch, P.W., Wilson, R.E., Brown, K., Hickson, I.D. and Emmerson, P.T. Complete nucleotide sequence of the Escherichia coli ptr gene encoding protease III. Nucleic Acids Res. 14 (1986) 7695–7703. [DOI] [PMID: 3534791]
2.  Affholter, J.A., Fried, V.A. and Roth, R.A. Human insulin-degrading enzyme shares structural and functional homologies with E. coli protease III. Science 242 (1988) 1415–1418. [DOI] [PMID: 3059494]
3.  Becker, A.B. and Roth, R.A. An unusual active site identified in a family of zinc metalloendopeptidases. Proc. Natl. Acad. Sci. USA 89 (1992) 3835–3839. [DOI] [PMID: 1570301]
4.  Ding, L., Becker, A.B., Suzuki, A. and Roth, R.A. Comparison of the enzymatic and biochemical properties of human insulin-degrading enzyme and Escherichia coli protease III. J. Biol. Chem. 267 (1992) 2414–2420. [PMID: 1733942]
5.  Anastasi, A., Knight, C.G. and Barrett, A.J. Characterization of the bacterial metalloendopeptidase pitrilysin by use of a continuous fluorescence assay. Biochem. J. 290 (1993) 601–607. [PMID: 7680857]
[EC 3.4.24.55 created 1992 as EC 3.4.99.44, transferred 1993 to EC 3.4.24.55 (EC 3.4.99.45 created 1992, incorporated 1993)]
 
 
EC 3.4.24.56     
Accepted name: insulysin
Reaction: Degradation of insulin, glucagon and other polypeptides. No action on proteins
Other name(s): insulinase; insulin-degrading enzyme; insulin protease; insulin proteinase; insulin-degrading neutral proteinase; insulin-specific protease; insulin-glucagon protease; metalloinsulinase; IDE
Comments: A 110 kDa cytosolic enzyme, known from mammals and the fruit fly, Drosophila melanogaster. Inhibited by bacitracin, chelating agents EDTA and 1,10-phenanthroline, and by thiol-blocking reagents such as N-ethylmaleimide, but not by phosphoramidon. In peptidase family M16 (pitrilysin family).
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 9013-83-6
References:
1.  Duckworth, W.C. Insulin degradation: mechanisms, products, and significance. Endocrine Rev. 9 (1988) 319–345. [DOI] [PMID: 3061785]
2.  Affholter, J.A., Hsieh, C.-L., Francke, U. and Roth, R.A. Insulin-degrading enzyme: stable expression of the human complementary DNA, characterization of its protein product, and chromosomal mapping of the human and mouse genes. Mol. Endocrinol. 4 (1990) 1125–1135. [DOI] [PMID: 2293021]
3.  Duckworth, W.C., Hamel, F.G., Bennett, R., Ryan, M.P. and Roth, R.A. Human red blood cell insulin-degrading enzyme and rat skeletal muscle insulin protease share antigenic sites and generate identical products from insulin. J. Biol. Chem. 265 (1990) 2984–2987. [PMID: 1689296]
4.  Kuo, W.-L., Gehm, B.D. and Rosner, M.R. Cloning and expression of the cDNA for a Drosophila insulin-degrading enzyme. Mol. Endocrinol. 4 (1990) 1580–1591. [DOI] [PMID: 2126597]
5.  Ding, L., Becker, A.B., Suzuki, A. and Roth, R.A. Comparison of the enzymatic and biochemical properties of human insulin-degrading enzyme and Escherichia coli protease III. J. Biol. Chem. 267 (1992) 2414–2420. [PMID: 1733942]
[EC 3.4.24.56 created 1972 as EC 3.4.99.10, transferred 1976 EC 3.4.22.11, transferred 1978 to EC 3.4.99.45, transferred 1993 to to EC 3.4.24.56 (EC 3.4.99.46 created 1992, incorporated 2000)]
 
 
EC 3.4.24.57     
Accepted name: O-sialoglycoprotein endopeptidase
Reaction: Hydrolysis of O-sialoglycoproteins; cleaves -Arg31┼Asp- bond in glycophorin A. Does not cleave unglycosylated proteins, desialylated glycoproteins or glycoproteins that are only N-glycosylated
Other name(s): glycoprotease; glycophorin A proteinase; glycoproteinase; sialoglycoprotease; sialoglycoproteinase
Comments: An enzyme secreted by the bacterium Pasteurella haemolytica. Inhibited by EDTA (100 mM) and 1,10-phenanthroline. Type example of peptidase family M22
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 129430-53-1
References:
1.  Abdullah, K.M., Lo, R.Y.C. and Mellors, A. Cloning, nucleotide sequence, and expression of the Pasteurella haemolytica A1 glycoprotease gene. J. Bacteriol. 173 (1991) 5597–5603. [DOI] [PMID: 1885539]
2.  Abdullah, K.M., Udoh, E.A., Shewen, P.E. and Mellors, A. A neutral glycoprotease of Pasteurella haemolytica A1 specifically cleaves O-sialoglycoproteins. Infect. Immun. 60 (1992) 56–62. [PMID: 1729196]
3.  Sutherland, D.R., Abdullah, K.M., Cyopick, P. and Mellors, A. Cleavage of the cell-surface O-sialoglycoproteins CD34, CD 43, CD 44, and CD45 by a novel glycoprotease from Pasteurella haemolytica. J. Immunol. 148 (1992) 1458–1464. [PMID: 1371528]
[EC 3.4.24.57 created 1993]
 
 
EC 3.4.24.58     
Accepted name: russellysin
Reaction: Specifically activates several components of the blood clotting system, including coagulation factor X, coagulation factor IX and protein C by cleavage of -Arg┼ bonds. Has no action on insulin B chain
Other name(s): Russell’s viper venom factor X activator, RVV-X; blood-coagulation factor X activating enzyme; metalloproteinase RVV-x; Vipera russelli proteinase; Russell’s viper blood coagulation factor X activator; RVV-V
Comments: This enzyme from the venom of Russell’s viper (Vipera russelli) of 79 kDa comprises a heavy (59 kDa) and a heterogeneous light (18-21 kDa) chain. Contains Ca2+ and Zn2+. The heavy chain contains the zinc-binding endopeptidase domain and a disintegrin. In peptidase family M12 (astacin family)
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 79393-92-3
References:
1.  Furie, B.C. and Furie, B. Coagulant protein of Russell's viper venom. Methods Enzymol. 45 (1976) 191–205. [DOI] [PMID: 1011991]
2.  Lindquist, P.A., Fujikawa, K. and Davie, E.W. Activation of bovine factor IX (Christmas factor) by factor XIa (activated plasma thromboplastin antecent) and a protease from Russell's viper venom. J. Biol. Chem. 253 (1978) 1902–1909. [PMID: 632245]
3.  Takeya, H., Nishida, S., Miyata, T., Kawada, S., Saisaka, Y., Morita, T. and Iwanaga, S. Coagulation factor X activating enzyme from Russell's viper venom (RVV-X). A novel metalloproteinase with disintegrin (platelet aggregation inhibitor)-like and C-type lectin-like domains. J. Biol. Chem. 267 (1992) 14109–14117. [PMID: 1629211]
[EC 3.4.24.58 created 1993]
 
 
EC 3.4.24.61     
Accepted name: nardilysin
Reaction: Hydrolysis of polypeptides, preferably at -Xaa┼Arg-Lys-, and less commonly at -Arg┼Arg-Xaa-, in which Xaa is not Arg or Lys
Other name(s): N-arginine dibasic convertase; NRD-convertase
Comments: Enzyme of 133 kDa from rat brain and testis. A homologue of pitrilysin containing the His-Phe-Leu-Glu-His zinc-binding sequence, and a highly acidic stretch of 71 residues. Unusually for a metalloendopeptidase, inhibited by bestatin, amastatin and N-ethylmaleimide. In peptidase family M16 (pitrilysin family)
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, CAS registry number: 292850-69-2
References:
1.  Gomez, S., Gluschankof, P., Morel, A. and Cohen, P. The somatostatin-28 convertase of rat brain cortex is associated with secretory granule membranes. J. Biol. Chem. 260 (1985) 10541–10545. [PMID: 3897221]
2.  Gluschankof, P., Gomez, S., Morel, A. and Cohen, P. Enzymes that process somatostatin precursors. A novel endoprotease that cleaves before the arginine-lysine doublet is involved in somatostatin-28 convertase activity of rat brain cortex. J. Biol. Chem. 262 (1987) 9615–9620. [PMID: 2885328]
3.  Chesneau, V., Pierotti, A.R., Barré, N., Créminon, C., Tougard, C. and Cohen, P. Isolation and characterization of a dibasic selective metalloendopeptidase from rat testes that cleaves at the amino terminus of arginine residues. J. Biol. Chem. 269 (1994) 2056–2061. [PMID: 8294457]
4.  Pierotti, A.R., Prat, A., Chesneau, V., Gaudoux, F., Leseney, A.-M., Foulon, T. and Cohen, P. N-Arginine dibasic convertase, a metalloendopeptidase as a prototype of a class of processing enzymes. Proc. Natl. Acad. Sci. USA 91 (1994) 6078–6082. [DOI] [PMID: 8016118]
[EC 3.4.24.61 created 1995]
 
 
EC 3.4.24.62     
Accepted name: magnolysin
Reaction: Hydrolysis of polypeptides with Arg or Lys in P1 and P2, e.g. to hydrolyse pro-oxytocin at -Lys-Arg┼Ala-Val-. The specificity further depends on the organization of a β-turn-α-helix of nine or more residues containing the paired basic amino acids near the centre [3]
Other name(s): bovine neurosecretory granule protease cleaving pro-oxytocin/neurophysin; pro-oxytocin/neurophysin convertase; prooxyphysin proteinase; pro-oxytocin convertase
Comments: An endopeptidase of 58 kDa known from bovine pituitary neurosecretory granules and bovine and human corpus luteum [4,5]. Inhibited by EDTA [1]
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, CAS registry number: 162875-09-4
References:
1.  Clamagirand, C., Creminon, C., Fahy, C., Boussetta, H. and Cohen, P. Partial purification and functional properties of an endoprotease from bovine neurosecretory granules cleaving proocytosin/neurophysin peptides at the basic amino acid doublet. Biochemistry 26 (1987) 6018–6023. [PMID: 2825769]
2.  Créminon, C., Rholam, M., Boussetta, H., Marrakchi, N. and Cohen, P. Synthetic peptide substrates as models to study a pro-ocytocin/neurophysin converting enzyme. J. Chromatogt. 440 (1988) 439–448. [PMID: 3042797]
3.  Brakch, N., Boussetta, H., Rholam, M. and Cohen, P. Processing endoprotease recognizes a structural feature at the cleavage site of peptide prohormones. The pro-ocytocin/neurophysin model. J. Biol. Chem. 264 (1989) 15912–15916. [PMID: 2674120]
4.  Plevrakis, I, Créminon, C., Clamagirand, C., Brakch, N., Rholam, M. and Cohen, P. Proocytocin/neurophysin convertase from bovine neurohypophysis and corpus luteum secretory granules: complete purification, structure-function relationships, and competitive inhibitor. Biochemistry 28 (1989) 2705–2710. [PMID: 2659078]
5.  Guillou, M.D., Camier, M. and Clamagirand, C. Evidence for the presence of pro-oxytocin/neurophysin converting enzyme in the human ovary. J. Endocrinol. 142 (1994) 345–352. [PMID: 7931007]
[EC 3.4.24.62 created 1995]
 
 
EC 3.4.24.64     
Accepted name: mitochondrial processing peptidase
Reaction: Release of N-terminal targetting peptides from precursor proteins imported into the mitochondrion, typically with Arg in position P2
Other name(s): processing enhancing peptidase (for one of two subunits); mitochondrial protein precursor-processing proteinase; matrix peptidase; matrix processing peptidase; matrix processing proteinase; mitochondrial protein precursor-processing proteinase; MPP
Comments: Known from the mitochondrial matrix of fungi and mammals. Formed from two subunits, both homologous with pitrilysin [3], and the products of the MAS1 and MAS2 genes in yeast. In peptidase family M16 (pitrilysin family).
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 86280-61-7
References:
1.  Jensen, R.E. and Yaffe, M.P. Import of proteins into yeast mitochondria: the nuclear MAS2 gene encodes a component of the processing protease that is homologous to the MAS1-encoded subunit. EMBO J. 7 (1988) 3863–3871. [PMID: 3061808]
2.  Witte, C., Jensen, R.E., Yaffe, M.P. and Schatz, G. MAS1, a gene essential for yeast mitochondrial assembly, encodes a subunit of the mitochondrial processing protease. EMBO J. 7 (1988) 1439–1447. [PMID: 3044780]
3.  Rawlings, N.D. and Barrett, A.J. Homologues of insulinase, a new superfamily of metalloendopeptidases. Biochem. J. 275 (1991) 389–391. [PMID: 2025223]
4.  Kalousek, F., Neupert, W., Omura, T., Schatz, G. and Schmitz, U.K. Uniform nomenclature for the mitochondrial peptidases cleaving precursors of mitochondrial proteins. Trends Biochem. Sci. 18 (1993) 249. [DOI] [PMID: 8212133]
5.  Brunner, M. and Neupert, W. Purification and characterization of the mitochondrial processing peptidase of Neurospora crassa. Methods Enzymol. 248 (1994) 717–728.
[EC 3.4.24.64 created 1989/90 as EC 3.4.99.41, transferred 1995 to EC 3.4.24.64]
 
 
EC 3.4.24.66     
Accepted name: choriolysin L
Reaction: Hydrolysis of the inner layer of fish egg envelope. Also hydrolysis of casein and small molecule substrates such as succinyl-Leu-Leu-Val-Tyr┼7-(4-methyl)coumarylamide
Other name(s): teleost hatching enzyme (component); low choriolytic enzyme (LCE)
Comments: Known from the teleost fish Oryzias latipes (medaka). Efficient dissolution of the egg membrane requires concerted action with choriolysin H. A 24 kDa peptidase family M12 (astacin family)
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, CAS registry number: 177529-15-6
References:
1.  Yasumasu, S., Iuchi, I. and Yamagami, K. Medaka hatching enzyme consists of two kinds of proteases which act cooperatively. Zool. Sci. 5 (1988) 191–195.
2.  Yasumasu, S., Iuchi, I. and Yamagami, K. Isolation and some properties of low choriolytic enzyme (LCE), a component of the hatching enzyme of the teleost, Oryzias latipes. J. Biochem. (Tokyo) 105 (1989) 212–218. [PMID: 2656665]
3.  Yasumasu, S., Katow, S., Hamazaki, T.S., Iuchi, I. and Yamagami, K. Two constituent proteases of a teleostean hatching enzyme: concurrent syntheses and packaging in the same secretory granules in discrete arrangement. Dev. Biol. 149 (1992) 349–356. [DOI] [PMID: 1730389]
4.  Yasumasu, S., Yamada, K., Akasaka, K., Mitsunaga, K., Iuchi, I., Shimada, H. and Yamagami, K. Isolation of cDNAs for LCE and HCE, two constituent proteases of the hatching enzyme of Oryzias latipes, and concurrent expression of their mRNAs during development. Dev. Biol. 153 (1992) 250–258. [DOI] [PMID: 1397682]
[EC 3.4.24.66 created 1995]
 
 
EC 3.4.24.67     
Accepted name: choriolysin H
Reaction: Hydrolysis of the inner layer of fish egg envelope. Also hydrolysis of casein and small molecule substrates such as succinyl-Leu-Leu-Val-Tyr┼7-(4-methyl)coumarylamide
Other name(s): teleost hatching enzyme (component); high choriolytic enzyme (HCE)
Comments: Known from the teleost fish Oryzias latipes (medaka). Efficient dissolution of the egg membrane requires concerted action with choriolysin L. A 25.5 kDa peptidase in family M12 (astacin family)
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, CAS registry number: 177529-16-7
References:
1.  Yamagami, K. Isolation of a choriolytic enzyme (hatching enzyme) of the teleost, Oryzias latipes. Dev. Biol. 29 (1972) 343–348. [DOI] [PMID: 4652273]
2.  Yasumasu, S., Iuchi, I. and Yamagami, K. Purification and partial characterization of high choriolytic enzyme (HCE), a component of the hatching enzyme of the teleost, Oryzias latipes. J. Biochem. (Tokyo) 105 (1989) 204–211. [PMID: 2656664]
3.  Yasumasu, S., Katow, S., Umino, Y., Iuchi, I. and Yamagami, K. A unique proteolytic action of HCE, a constituent protease of a fish hatching enzyme: tight binding to its natural substrate, egg envelope. Biochem. Biophys. Res. Commun. 162 (1989) 58–63. [DOI] [PMID: 2751672]
4.  Yasumasu, S., Yamada, K., Akasaka, K., Mitsunaga, K., Iuchi, I., Shimada, H. and Yamagami, K. Isolation of cDNAs for LCE and HCE, two constituent proteases of the hatching enzyme of Oryzias latipes, and concurrent expression of their mRNAs during development. Dev. Biol. 153 (1992) 250–258. [DOI] [PMID: 1397682]
5.  Lee, K.S., Yasumasu, S., Nomura, K. and Iuchi, I. HCE, a constituent of the hatching enzymes of Oryzias latipes embryos, releases unique proline-rich polypeptides from its natural substrate, the hardened chorion. FEBS Lett. 339 (1993) 281–284. [DOI] [PMID: 8112467]
[EC 3.4.24.67 created 1995]
 
 
EC 3.4.24.68     
Accepted name: tentoxilysin
Reaction: Hydrolysis of -Gln76┼Phe- bond in synaptobrevin (also known as neuronal vesicle-associated membrane protein, VAMP)
Other name(s): tetanus neurotoxin
Comments: Zinc enzyme produced by Clostridium tetani. Proenzyme of 150 kDa is processed to disulfide-linked subunits of 100 and 50 kDa, the latter being responsible for the endopeptidase activity. Weakly inhibited by captopril, and phosphoramidon. The clostridial neurotoxins disable the neuroexocytosis apparatus, and have been described as the most toxic substances known. Tentoxilysin acts at the spinal inhibitory interneurons, blocking the release of various neurotransmitters to produce spastic paralysis. Type example of peptidase family M27 (tentoxilysin family)
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 107231-12-9
References:
1.  Fujii, N., Kimura, K., Yashiki, T., Tsuzuki, K., Moriishi, K., Yokosawa, N., Syuto, B. and Oguma, K. A zinc-protease specific domain in botulinum and tetanus neurotoxins. Microbiol. Intern. 36 (1992) 213–220. [DOI] [PMID: 1376283]
2.  Schiavo, G., Benfenati, F., Poulain, B., Rossetto, O., Polverino de Laureto, P., DasGupta, B.R. and Montecucco, C. Tetanus and botulinum-B neurotoxins block neurotransmitter release by proteolytic cleavage of synaptobrevin. Nature 359 (1992) 832–834. [DOI] [PMID: 1331807]
3.  Schiavo, G., Rossetto, O., Santucci, A., DasGupta, B.R. and Montecucco, C. Botulinum neurotoxins are zinc proteins. J. Biol. Chem. 267 (1992) 23479–23483. [PMID: 1429690]
4.  Montecucco, C. and Schiavo, G. Mechanism of action of tetanus and botulinum neurotoxins. Mol. Microbiol. 8 (1994) 1–13. [DOI] [PMID: 7527117]
5.  Schiavo, G. and Montecucco, C. Tetanus and botulism neurotoxins. Methods Enzymol. 248 (1995) 643–652. [PMID: 7674951]
[EC 3.4.24.68 created 1995]
 
 
EC 3.4.24.70     
Accepted name: oligopeptidase A
Reaction: Hydrolysis of oligopeptides, with broad specificity. Gly or Ala commonly occur as P1 or P1′ residues, but more distant residues are also important, as is shown by the fact that Z-Gly-Pro-Gly┼Gly-Pro-Ala is cleaved, but not Z-(Gly)5 [4]
Other name(s): 68000-M signalpeptide hydrolase
Comments: Known from Escherichia coli and Salmonella typhimurium. A zinc metallopeptidase, in peptidase family M3 (thimet oligopeptidase family), but differs from thimet oligopeptidase in lack of thiol-activation
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, CAS registry number: 394250-11-4
References:
1.  Novak, P. and Dev, I.K. Degradation of a signal peptide by protease IV and oligopeptidase A. J. Bacteriol. 170 (1988) 5067–5075. [DOI] [PMID: 3053642]
2.  Conlin, C.A., Vimr, E.R. and Miller, C.G. Oligopeptidase A is required for normal phage P22 development. J. Bacteriol. 174 (1992) 5869–5880. [DOI] [PMID: 1522065]
3.  Conlin, C.A., Trun, N.J., Silhavy, T.J. and Miller, C.G. Escherichia coli prlC encodes an endopeptidase and is homologous to the Salmonella typhimurium opdA gene. J. Bacteriol. 174 (1992) 5881–5887. [DOI] [PMID: 1325967]
4.  Conlin, C.A. and Miller, C.G. Oligopeptidase A and peptidyl-dipeptidase of Escherichia and Salmonella. Methods Enzymol. 248 (1995) 567–579. [PMID: 7674945]
[EC 3.4.24.70 created 1996]
 
 
EC 3.4.24.71     
Accepted name: endothelin-converting enzyme 1
Reaction: Hydrolysis of the -Trp21┼Val- bond in big endothelin to form endothelin 1
Other name(s): endothelin-converting enzyme; ECE-1
Comments: A phosphoramidon-sensitive metalloendopeptidase in peptidase family M13 (neprilysin family). An integral membrane protein predominantly of endothelial cells, which generates the potent vasoconstrictor endothelin 1 from its inactive precursor
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 138238-81-0
References:
1.  Takahashi, M., Matsushita, Y., Iijima, Y. and Tanzawa, K. Purification and characterization of endothelin-converting enzyme from rat lung. J. Biol. Chem. 268 (1993) 21394–21398. [PMID: 8407980]
2.  Shimada, K., Takahashi, M. and Tanzawa, K. Cloning and functional expression of endothelin-converting enzyme from rat endothelial cells. J. Biol. Chem. 269 (1994) 18275–18278. [PMID: 8034569]
3.  Xu, D., Emoto, N., Giaid, A., Slaughter, C., Kaw, S., DeWit, D. and Yanagisawa, M. ECE-1: A membrane-bound metalloprotease that catalyzes the proteolytic activation of big endothelin-1. Cell 78 (1994) 473–485. [DOI] [PMID: 8062389]
[EC 3.4.24.71 created 1996]
 
 
EC 3.4.24.73     
Accepted name: jararhagin
Reaction: Hydrolysis of -His10┼Leu-, -Ala14┼Leu-, -Tyr16┼Leu-and -Phe24┼Phe- bonds in insulin B chain
Other name(s): HF2-proteinase; JF1
Comments: Hemorrhagic endopeptidase from the venom of the jararaca snake (Bothrops jararaca). The 52-kDa enzyme contains a disintegrin domain [3]. In peptidase family M12 (astacin family)
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 160477-79-2
References:
1.  Mandelbaum, F.R., Reichl, A.P. and Assakura, M.T. Some physical and biochemical characteristics of HF2, one of the hemorrhagic factors in the venom of Bothrops jararaca. In: Ohsaka, A., Hayashi, K. and Sawai, Y. (Eds), Animal, Plant and Microbial Toxins, Plenum Press, New York, 1976, pp. 111–121.
2.  Assakura, M.T., Reichl, A.P. and Mandelbaum, F.R. Comparison of immunological, biochemical and biophysical properties of three hemorrhagic factors isolated from the venom of Bothrops jararaca (jararaca). Toxicon 24 (1986) 943–946. [DOI] [PMID: 3810664]
3.  Paine, M.J.I., Desmond, H.P., Theakston, R.D.G. and Crampton, J.M. Purification, cloning, and molecular characterization of a high molecular weight hemorrhagic metalloprotease, jararhagin, from Bothrops jararaca venom. Insights into the disintegrin gene family. J. Biol. Chem. 267 (1992) 22869–22876. [PMID: 1385408]
[EC 3.4.24.73 created 1996]
 
 
EC 3.4.24.74     
Accepted name: fragilysin
Reaction: Broad proteolytic specificity, bonds hydrolysed including -Gly┼Leu-, -Met┼Leu-, -Phe┼Leu-, -Cys┼Leu-, Leu┼Gly
Other name(s): Bacteroides fragilis (entero)toxin
Comments: Thought to be a cause of diarrhoea in animals and humans. Hydrolyses extracellular matrix proteins, and disrupts tight junctions of intestinal epithelial cells. Also degrades intracellular, cytoskeletal proteins actin, myosin and others. In peptidase family M10 (interstitial collagenase family)
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, CAS registry number: 188596-63-6
References:
1.  Moncrief, J.S., Obiso, R., Jr., Barroso, L.A., Kling, J.J., Wright, R.L., Van Tassell, R.L., Lyerly, D.M. and Wilkins, T.D. The enterotoxin of Bacteroides fragilis is a metalloprotease. Infect. Immun. 63 (1995) 175–181. [PMID: 7806355]
2.  Obiso, R.J., Jr., Lyerly, D.M., Van Tassell, R.L. and Wilkins, T.D. Proteolytic activity of the Bacteroides fragilis enterotoxin causes fluid secretion and intestinal damage in vivo. Infect. Immun. 63 (1995) 3820–3826. [PMID: 7558286]
3.  Donelli, G., Fabbri, A. and Fiorentini, C. Bacteroides fragilis enterotoxin induces cytoskeletal changes and surface blebbing in HT-29 cells. Infect. Immun. 64 (1996) 113–119. [PMID: 8557328]
4.  Koshy, S.S., Montrose, M.H. and Sears, C.L. Human intestinal epithelial cells swell and demonstrate actin rearrangement in response to the metalloprotease toxin of Bacteroides fragilis. Infect. Immun. 64 (1996) 5022–5028. [PMID: 8945541]
5.  Kling, J.J., Wright, R.L., Moncrief, J.S. and Wilkins, T.D. Cloning and characterization of the gene for the metalloprotease enterotoxin of Bacteroides fragilis. FEMS Microbiol. Lett. 146 (1997) 279–284. [DOI] [PMID: 9011050]
[EC 3.4.24.74 created 1997]
 
 
EC 3.4.24.77     
Accepted name: snapalysin
Reaction: Hydrolyses proteins with a preference for Tyr or Phe in the P1′ position. Has no action on amino-acid p-nitroanilides
Other name(s): small neutral protease; SnpA gene product (Streptomyces lividans)
Comments: Type example of peptidase family M7.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 945859-47-2
References:
1.  Kurisu, G., Sugimoto, A., Harada, S., Takagi, M., Imanaka, T. and Kai, Y. Characterization of a small metalloprotease from Streptomyces caespitosus with high specificity to aromatic residues. J. Ferment. Bioeng. 83 (1997) 590–592.
2.  Butler, M.J. Snapalysin. In: Barrett, A.J., Rawlings, N.D. and Woessner, J.F. (Eds), Handbook of Proteolytic Enzymes, Handbook of Proteolytic Enzymes, London, 1998, pp. 1134–1135.
3.  Kurisu, G., Kai, Y. and Harada, S. Structure of the zinc-binding site in the crystal structure of a zinc endoprotease from Streptomyces caespitosus at 1 Å resolution. J. Inorg. Biochem. 82 (2000) 225–228. [DOI] [PMID: 11132632]
[EC 3.4.24.77 created 2001]
 
 
EC 3.4.24.78     
Accepted name: gpr endopeptidase
Reaction: Endopeptidase action with P4 Glu or Asp, P1 preferably Glu > Asp, P1′ hydrophobic and P2′ Ala
Other name(s): germination proteinase
Comments: Initiates the degradation of small, acid-soluble proteins during spore germination in Bacillus megaterium. Type example of peptidase family M63.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, SWISSPROT, CAS registry number: 75718-32-0
References:
1.  Ponnuraj, K., Rowland, S., Nessi, C., Setlow, P. and Jedrzejas, M.J. Crystal structure of a novel germination protease from spores of Bacillus megaterium: Structural arrangement and zymogen activation. J. Mol. Biol. 300 (2000) 1–10. [DOI] [PMID: 10864493]
[EC 3.4.24.78 created 2003]
 
 
EC 3.4.24.79     
Accepted name: pappalysin-1
Reaction: Cleavage of the Met135┼Lys bond in insulin-like growth factor binding protein (IGFBP)-4, and the Ser143┼Lys bond in IGFBP-5
Other name(s): insulin-like growth factor binding protein-4 protease; pregnancy-associated plasma protein-A
Comments: A 400-kDa disulfide-linked dimer. Circulates in human pregnancy mainly as a complex with the proform of eosinophil major basic protein, which acts as an inhibitor of the peptidase. The rate of hydrolysis of IGFBP-4 is increased about 20-fold by the presence of insulin-like growth factor (IGF), whereas that of IGFBP-5 is decreased about two-fold. In peptidase family M43.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, SWISSPROT
References:
1.  Lawrence, J.B., Oxvig, C., Overgaard, M.T., Sottrup-Jensen, L., Gleich, G.J. , Hays L.G., Yates, J.R. 3rd, and Conover, C.A. The insulin-like growth factor (IGF)-dependent IGF binding protein-4 protease secreted by human fibroblasts is pregnancy-associated plasma protein-A. Proc. Natl. Acad. Sci. USA 96 (1999) 3149–3153. [DOI] [PMID: 10077652]
2.  Chen, B.K., Overgaard, M.T., Bale, L.K., Resch, Z.T., Christiansen, M., Oxvig, C. and Conover, C.A. Molecular regulation of the IGF-binding protein-4 protease system in human fibroblasts: identification of a novel inducible inhibitor. Endocrinology 143 (2002) 1199–1205. [DOI] [PMID: 11897673]
[EC 3.4.24.79 created 2003]
 
 
EC 3.4.24.85     
Accepted name: S2P endopeptidase
Reaction: Cleaves several transcription factors that are type-2 transmembrane proteins within membrane-spanning domains. Known substrates include sterol regulatory element-binding protein (SREBP) -1, SREBP-2 and forms of the transcriptional activator ATF6. SREBP-2 is cleaved at the site DRSRILL483CVLTFLCLSFNPLTSLLQWGGA, in which the membrane-spanning segment is underlined. The residues NP (bold), 11 residues distal to the site of cleavage in the membrane-spanning domain, are important for cleavage by S2P endopeptidase. Replacement of either of these residues does not prevent cleavage, but there is no cleavage if both of these residues are replaced.
Comments: Type example of peptidase family M50. The transcription factors SREBP-1 and -2 are synthesized as precursor proteins that are attached to the membranes of the endoplasmic reticulum and two cleavages are needed to release the active factor so that it can move to the nucleus. This enzyme cleaves the second of these, and is thus the "site 2 protease", S2P.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, SWISSPROT, CAS registry number: 752251-31-3
References:
1.  Brown, M.S., Ye, J., Rawson, R.B. and Goldstein, J.L. Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans. Cell 100 (2000) 391–398. [DOI] [PMID: 10693756]
[EC 3.4.24.85 created 2003]
 
 
EC 3.4.24.87     
Accepted name: ADAMTS13 endopeptidase
Reaction: The enzyme cleaves the von Willebrand factor at bond Tyr842┼Met843 within the A2 domain
Other name(s): ADAMTS VWF cleaving metalloprotease; ADAMTS-13; ADAMTS13; vWF-cleaving protease; VWF-CP; vWF-degrading protease; Upshaw factor; von Willebrand factor cleaving protease; ADAMTS13 peptidase
Comments: In peptidase family M12.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS
References:
1.  Fujikawa, K., Suzuki, H., McMullen, B. and Chung, D. Purification of human von Willebrand factor-cleaving protease and its identification as a new member of the metalloproteinase family. Blood 98 (2001) 1662–1666. [PMID: 11535495]
2.  Dong, J.F., Moake, J.L., Nolasco, L., Bernardo, A., Arceneaux, W., Shrimpton, C.N., Schade, A.J., McIntire, L.V., Fujikawa, K. and Lopez, J.A. ADAMTS-13 rapidly cleaves newly secreted ultralarge von Willebrand factor multimers on the endothelial surface under flowing conditions. Blood 100 (2002) 4033–4039. [DOI] [PMID: 12393397]
[EC 3.4.24.87 created 2009]
 
 
EC 3.4.24.88      
Transferred entry: desampylase. Transferred to EC 3.4.19.15 desampylase
[EC 3.4.24.88 created 2015, deleted 2016]
 
 
EC 3.4.24.89     
Accepted name: Pro-Pro endopeptidase
Reaction: The enzyme catalyses the hydrolytic cleavage of peptide bonds between two proline residues
Other name(s): metalloprotease CD2830
Comments: This metalloprotease, which is secreted by the bacterium Peptoclostridium difficile, contains zinc.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc
References:
1.  Cafardi, V., Biagini, M., Martinelli, M., Leuzzi, R., Rubino, J.T., Cantini, F., Norais, N., Scarselli, M., Serruto, D. and Unnikrishnan, M. Identification of a novel zinc metalloprotease through a global analysis of Clostridium difficile extracellular proteins. PLoS One 8:e81306 (2013). [DOI] [PMID: 24303041]
2.  Hensbergen, P.J., Klychnikov, O.I., Bakker, D., van Winden, V.J., Ras, N., Kemp, A.C., Cordfunke, R.A., Dragan, I., Deelder, A.M., Kuijper, E.J., Corver, J., Drijfhout, J.W. and van Leeuwen, H.C. A novel secreted metalloprotease (CD2830) from Clostridium difficile cleaves specific proline sequences in LPXTG cell surface proteins. Mol. Cell. Proteomics 13 (2014) 1231–1244. [DOI] [PMID: 24623589]
3.  Hensbergen, P.J., Klychnikov, O.I., Bakker, D., Dragan, I., Kelly, M.L., Minton, N.P., Corver, J., Kuijper, E.J., Drijfhout, J.W. and van Leeuwen, H.C. Clostridium difficile secreted Pro-Pro endopeptidase PPEP-1 (ZMP1/CD2830) modulates adhesion through cleavage of the collagen binding protein CD2831. FEBS Lett. 589 (2015) 3952–3958. [DOI] [PMID: 26522134]
[EC 3.4.24.89 created 2015]
 
 
EC 3.4.25.1     
Accepted name: proteasome endopeptidase complex
Reaction: Cleavage of peptide bonds with very broad specificity
Other name(s): ingensin; macropain; multicatalytic endopeptidase complex; prosome; multicatalytic proteinase (complex); MCP; proteasome; large multicatalytic protease; multicatalytic proteinase; proteasome organelle; alkaline protease; 26S protease; tricorn proteinase; tricorn protease
Comments: A 20-S protein composed of 28 subunits arranged in four rings of seven. The outer rings are composed of α subunits, but the β subunits forming the inner rings are responsible for peptidase activity. In eukaryotic organisms there are up to seven different types of β subunits, three of which may carry the N-terminal threonine residues that are the nucleophiles in catalysis, and show different specificities. The molecule is barrel-shaped, and the active sites are on the inner surfaces. Terminal apertures restrict access of substrates to the active sites. There is evidence that catalytic subunits are replaced by others under some conditions so as to alter the specificity of proteolysis, perhaps optimizing it for the formation of antigenic peptides. A complex of the 20-S proteasome endopeptidase complex with a 19-S regulatory unit is the 26-S proteasome that degrades ubiquitin-protein conjugates. Type example of peptidase family T1.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS, PDB, CAS registry number: 140879-24-9
References:
1.  Seemüller, E., Lupas, A., Stock, D., Löwe, J., Huber, R. and Baumeister, W. Proteasome from Thermoplasma acidophilum: a threonine protease. Science 268 (1995) 579–582. [DOI] [PMID: 7725107]
2.  Coux, O., Tanaka, K. and Goldberg, A.L. Structure and functions of the 20S and 26S proteasomes. Annu. Rev. Biochem. 65 (1996) 801–847. [DOI] [PMID: 8811196]
3.  Groll, M., Ditzel, L., Löwe, J., Stock, D., Bochtler, M., Bartunik, H.D. and Huber, R. Structure of 20S proteasome from yeast at 2.4Å resolution. Nature 386 (1997) 463–471. [DOI] [PMID: 9087403]
4.  Dick, T.P., Nussbaum, A.K., Deeg, M., Heinemeyer, W., Groll, M., Schirle, M., Keilholz, W., Stevanovic, S., Wolf, D.H., Huber, R., Rammensee, H.G. and Schild, H. Contribution of proteasomal β-subunits to the cleavage of peptide substrates analyzed with yeast mutants. J. Biol. Chem. 273 (1998) 25637–25646. [DOI] [PMID: 9748229]
[EC 3.4.25.1 created 1978 as EC 3.4.24.5, part transferred 1989 to EC 3.4.22.21, transferred 1992 to EC 3.4.99.46, transferred 2000 to EC 3.4.25.1]
 
 
EC 3.4.25.2     
Accepted name: HslU—HslV peptidase
Reaction: ATP-dependent cleavage of peptide bonds with broad specificity.
Other name(s): HslUV; HslV-HslU; HslV peptidase; ATP-dependent HslV-HslU proteinase; caseinolytic protease X; caseinolytic proteinase X; ClpXP ATP-dependent protease; ClpXP protease; ClpXP serine proteinase; Escherichia coli ClpXP serine proteinase; HslUV protease; HslUV proteinase; HslVU protease; HslVU proteinase; protease HslVU; proteinase HslUV
Comments: The HslU subunit of the HslU—HslV complex functions as an ATP dependent ’unfoldase’. The binding of ATP and its subsequent hydrolysis by HslU are essential for unfolding of protein substrates subsequently hydrolysed by HslV [5]. HslU recognizes the N-terminal part of its protein substrates and unfolds these before they are guided to HslV for hydrolysis [7]. In peptidase family T1.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, MEROPS
References:
1.  Wang, J., Rho, S.H., Park, H.H. and Eom, S.H. Correction of X-ray intensities from an HslV-HslU co-crystal containing lattice-translocation defects. Acta Crystallogr. D Biol. Crystallogr. 61 (2005) 932–941. [DOI] [PMID: 15983416]
2.  Nishii, W. and Takahashi, K. Determination of the cleavage sites in SulA, a cell division inhibitor, by the ATP-dependent HslVU protease from Escherichia coli. FEBS Lett. 553 (2003) 351–354. [DOI] [PMID: 14572649]
3.  Ramachandran, R., Hartmann, C., Song, H.K., Huber, R. and Bochtler, M. Functional interactions of HslV (ClpQ) with the ATPase HslU (ClpY). Proc. Natl. Acad. Sci. USA 99 (2002) 7396–7401. [DOI] [PMID: 12032294]
4.  Yoo, S.J., Seol, J.H., Shin, D.H., Rohrwild, M., Kang, M.S., Tanaka, K., Goldberg, A.L. and Chung, C.H. Purification and characterization of the heat shock proteins HslV and HslU that form a new ATP-dependent protease in Escherichia coli. J. Biol. Chem. 271 (1996) 14035–14040. [DOI] [PMID: 8662828]
5.  Yoo, S.J., Seol, J.H., Seong, I.S., Kang, M.S. and Chung, C.H. ATP binding, but not its hydrolysis, is required for assembly and proteolytic activity of the HslVU protease in Escherichia coli. Biochem. Biophys. Res. Commun. 238 (1997) 581–585. [DOI] [PMID: 9299555]
6.  Kanemori, M., Nishihara, K., Yanagi, H. and Yura, T. Synergistic roles of HslVU and other ATP-dependent proteases in controlling in vivo turnover of σ32 and abnormal proteins in Escherichia coli. J. Bacteriol. 179 (1997) 7219–7225. [DOI] [PMID: 9393683]
7.  Burton, R.E., Baker, T.A. and Sauer, R.T. Nucleotide-dependent substrate recognition by the AAA+ HslUV protease. Nat. Struct. Mol. Biol. 12 (2005) 245–251. [DOI] [PMID: 15696175]
[EC 3.4.25.2 created 2009, modified 2010]
 
 
EC 3.6.4.10     
Accepted name: non-chaperonin molecular chaperone ATPase
Reaction: ATP + H2O = ADP + phosphate
Other name(s): molecular chaperone Hsc70 ATPase
Systematic name: ATP phosphohydrolase (polypeptide-polymerizing)
Comments: This is a highly diverse group of enzymes that perform many functions that are similar to those of chaperonins. They comprise a number of heat-shock-cognate proteins. They are also active in clathrin uncoating and in the oligomerization of actin.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc
References:
1.  Sadis, S. and Hightower, L.E. Unfolded proteins stimulate molecular chaperone Hsc70 ATPase by accelerating ADP/ATP exchange. Biochemistry 31 (1992) 9406–9412. [PMID: 1356434]
2.  Blond-Elquindi, S., Fourie, A.M., Sambrook, J.F. and Gething, M.J. Peptide-dependent stimulation of the ATPase activity of the molecular chaperone BiP is the result of conversion of oligomers to active monomers. J. Biol. Chem. 268 (1993) 12730–12735. [PMID: 8509407]
3.  Wawrzynow, A., Wojtkowiak, D., Marszalek, J., Banecki, B., Jonsen, M., Graves, B., Georgopoulos, C. and Zylicz, M. The ClpX heat-shock protein of Escherichia coli, the ATP-dependent substrate specificity component of the ClpP-ClpX protease, is a novel molecular chaperone. EMBO J. 14 (1995) 1867–1877. [PMID: 7743994]
4.  Sriram, M., Osipiuk, J., Freeman, B., Morimoto, R. and Joachimiak, A. Human Hsp70 molecular chaperone binds two calcium ions within the ATPase domain. Structure 5 (1997) 403–414. [DOI] [PMID: 9083109]
5.  Li, X., Su, R.T., Hsu, H.T. and Sze, H. The molecular chaperone calnexin associated with the vacuolar H+-ATPase from oat seedlings. Plant Cell 10 (1998) 119–130. [PMID: 9477575]
[EC 3.6.4.10 created 2000]
 
 


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