Accepted name: peptidyl-dipeptidase A
Reaction: Release of a C-terminal dipeptide, oligopeptide┼Xaa-Yaa, when Xaa is not Pro, and Yaa is neither Asp nor Glu. Thus, conversion of angiotensin I to angiotensin II, with increase in vasoconstrictor activity, but no action on angiotensin II
Glossary: captopril = (2S)-1-(2-methyl-3-sulfanylpropanoyl)-L-proline
Other name(s): dipeptidyl carboxypeptidase I; peptidase P; dipeptide hydrolase (ambiguous); peptidyl dipeptidase; angiotensin converting enzyme; kininase II; angiotensin I-converting enzyme; carboxycathepsin; dipeptidyl carboxypeptidase; peptidyl dipeptidase I; peptidyl-dipeptide hydrolase; peptidyldipeptide hydrolase; endothelial cell peptidyl dipeptidase; ACE; peptidyl dipeptidase-4; PDH; peptidyl dipeptide hydrolase; DCP
Comments: A Cl--dependent, zinc glycoprotein that is generally membrane-bound. A potent inhibitor is captopril. Important in elevation of blood pressure, through formation of angiotensin II (vasoconstrictor) and destruction of bradykinin (vasodilator). Two molecular forms exist in mammalian tissues, a widely-distributed somatic form of 150- to 180-kDa that contains two non-identical catalytic sites, and a testicular form of 90- to 100-kDa that contains only a single catalytic site. Type example of peptidase family M2
1.  Soubrier, F., Alhenc-Gelas, F., Hubert, C., Allegrini, J., John, M., Tregear, G. and Corvol, P. Two putative active centers in human angiotensin I-converting enzyme revealed by molecular cloning. Proc. Natl. Acad. Sci. USA 85 (1988) 9386–9390. [PMID: 2849100]
2.  Ehlers, M.R.W., Fox, E.A., Strydom, D.J. and Riordan, J.F. Molecular cloning of human testicular angiotensin-converting enzyme: the testis enzyme is identical to the C-terminal half of endothelial angiotensin-converting enzyme. Proc. Natl. Acad. Sci. USA 86 (1989) 7741–7745. [PMID: 2554286]
3.  Wei, L., Clauser, E., Alhenc-Gelas, F. and Corvol, P. The two homologous domains of human angiotensin I-converting enzyme interact differently with competitive inhibitors. J. Biol. Chem. 267 (1992) 13398–13405. [PMID: 1320019]
4.  Corvol, P., Williams, T.A. and Soubrier, F. Peptidyl dipeptidase A: angiotensin I-converting enzyme. Methods Enzymol. 248 (1995) 283–305. [PMID: 7674927]
[EC created 1972, modified 1981, modified 1989, modified 1996, modified 2011]
Accepted name: peptidyl-dipeptidase Dcp
Reaction: Hydrolysis of unblocked, C-terminal dipeptides from oligopeptides, with broad specificity. Does not hydrolyse bonds in which P1′ is Pro, or both P1 and P1′ are Gly
Other name(s): dipeptidyl carboxypeptidase (Dcp); dipeptidyl carboxypeptidase
Comments: Known from Escherichia coli and Salmonella typhimurium. A zinc metallopeptidase in peptidase family M3 (thimet oligopeptidase family). Ac-Ala┼Ala-Ala is a good test substrate [3]. Inhibited by captopril, as is peptidyl-dipeptidase A. Formerly EC, and included in EC, peptidyl-dipeptidase A.
1.  Yaron, A. Dipeptidyl carboxypeptidase from Escherichia coli. Methods Enzymol. 45 (1976) 599–610. [PMID: 13271]
2.  Henrich, B., Becker, S., Schroeder, U. and Plapp, R. dcp gene of Escherichia coli: cloning, sequencing, transcript mapping, and characterization of the gene product. J. Bacteriol. 175 (1993) 7290–7300. [PMID: 8226676]
3.  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 created 1981 as EC, modified 1989, transferred 1996 to EC]
Accepted name: dactylysin
Reaction: Hydrolysis of peptides of at least six residues, with bulky hydrophobic residues in the P1′ position. Shows a preference for hydrophobic doublets such as -Phe┼Phe- and -Phe┼Leu- in somatostatin-(1-14)-peptide and dynorphin A-(1-6)-peptide, respectively
Other name(s): peptide hormone inactivating endopeptidase; PHIE
Comments: An endopeptidase of 100 kDa secreted from the skin of the amphibian, Xenopus laevis (Dactylêtre du Cap). Resembles neprilysin in insensitivity to 1 μM captopril, but differs from it in being insensitive to thiorphan (1 μM) and unable to digest [Met5]enkephalin, [Leu5]enkephalin, oxytocin, and substance P-(7-11)-peptide. A similar endopeptidase is found in human neuroblastoma cells [2]
1.  Carvalho, K.M., Joudiou, C., Boussetta, H., Leseney, A.-M. and Cohen, P. A peptide-hormone-inactivating endopeptidase in Xenopus laevis skin secretion. Proc. Natl. Acad. Sci. USA 89 (1992) 84–88. [PMID: 1729723]
2.  Delporte, C., Carvalho, K.M., Leseney, A.-M., Winand, J., Christophe, J. and Cohen, P. A new metallo-endopeptidase from human neuroblastoma NB-OK-1 cells which inactivates atrial natriuretic peptide by selective cleavage at the Ser123-Phe124 bond. Biochem. Biophys. Res. Commun. 182 (1992) 158–164. [PMID: 1531011]
3.  Joudiou, C., Carvalho, K.M., Camarao, G., Boussetta, H. and Cohen, P. Characterization of the thermolysin-like cleavage of biologically active peptides by Xenopus laevis peptide hormone inactivating enzyme. Biochemistry 32 (1993) 5959–5966. [PMID: 8507636]
[EC created 1995]
Accepted name: meprin B
Reaction: Hydrolysis of proteins, including azocasein, and peptides. Hydrolysis of -His5┼Leu-, -Leu6┼Cys-, -Ala14┼Leu- and -Cys19┼Gly- bonds in insulin B chain
Other name(s): meprin-b
Comments: A brush border membrane-bound metalloendopeptidase known from the intestine of all mouse strains that have been tested, and the kidney of certain inbred strains. A tetramer of meprin β subunits (in contrast to meprin A, which contains both α and β subunits). Occurs in the kidney as a proenzyme that can be activated by trypsin. Meprin B is inhibited by both EDTA and 1,10-phenanthroline, but not by phosphoramidon, captopril or thiorphan. In peptidase family M12 (astacin family)
1.  Kounnas, M.Z., Wolz, R.L., Gorbea, C.M. and Bond, J.S. Meprin-A and -B. Cell surface endopeptidases of the mouse kidney. J. Biol. Chem. 266 (1991) 17350–17357. [PMID: 1894622]
2.  Gorbea, C.M., Marchand, P., Jiang, W., Copeland, N.G., Gilbert, D.J., Jenkins, N.A. and Bond, J.S. Cloning, expression, and chromosomal localization of the mouse meprin β subunit. J. Biol. Chem. 268 (1993) 21035–21043. [PMID: 8407940]
3.  Johnson, G.D. and Hersh, L.B. Expression of meprin subunit precursors. Membrane anchoring through the β subunit and mechanism of zymogen activation. J. Biol. Chem. 269 (1994) 7682–7688. [PMID: 7510289]
4.  Wolz, R.L. and Bond, J.S. Meprins A and B. Methods Enzymol. 248 (1995) 325–345. [PMID: 7674930]
[EC created 1995]
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)
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. [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. [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. [PMID: 7527117]
5.  Schiavo, G. and Montecucco, C. Tetanus and botulism neurotoxins. Methods Enzymol. 248 (1995) 643–652. [PMID: 7674951]
[EC created 1995]
Accepted name: bontoxilysin
Reaction: Limited hydrolysis of proteins of the neuroexocytosis apparatus, synaptobrevin (also known as neuronal vesicle-associated membrane protein, VAMP), synaptosome-associated protein of 25 kDa (SNAP25) or syntaxin. No detected action on small molecule substrates
Other name(s): botulinum neurotoxin; BoNT
Comments: This zinc enzyme, produced by Clostridium botulinum, occurs as forms A-G that differ in specificity of action on the proteins of the neuroexocytosis apparatus [1-5]. The 150-kDa proenzymes of bontoxilysin are processed to disulfide-linked subunits of 100 and 50 kDa, the latter being responsible for the endopeptidase activities. Weakly inhibited by captopril, and phosphoramidon. Toxicity is due to action at the neuromuscular junctions that blocks release of acetylcholine, causing flaccid paralysis, in contrast to the spastic paralysis caused by tentoxilysin. In peptidase family M27 (tentoxilysin family)
1.  Schiavo, G., Rossetto, O., Catsicas, S., Polverino De Laureto, P., DasGupta, B.R., Benfenati, F. and Montecucco, C. Identification of the nerve-terminal targets of botulinum neurotoxins serotypes A, D and E. J. Biol. Chem. 268 (1993) 23784–23787. [PMID: 8226912]
2.  Schiavo, G., Santucci, A., DasGupta, B.R., Mehta, P.P., Jontes, J., Benfenati, F., Wilson, M.C. and Montecucco, C. Botulinum neurotoxins serotypes A and E cleave SNAP-25 at distinct COOH-terminal peptide bonds. FEBS Lett. 335 (1993) 99–103. [PMID: 8243676]
3.  Schiavo, G., Shone, C.C., Rossetto, O., Alexander, F.C.G. and Montecucco, C. Botulinum neurotoxin serotype F is a zinc endopeptidase specific for VAMP/synaptobrevin. J. Biol. Chem. 268 (1993) 11516–11519. [PMID: 8505288]
4.  Schiavo, G., Malizio, C., Trimble, W.S., Polverino De Laureto, P., Milan, G., Sugiyama, H., Johnson, E.A. and Montecucco, C. Botulinum G neurotoxin cleaves VAMP/synaptobrevin at a single Ala-Ala peptide bond. J. Biol. Chem. 269 (1994) 20213–20216. [PMID: 8051110]
5.  Montecucco, C. and Schiavo, G. Mechanism of action of tetanus and botulinum neurotoxins. Mol. Microbiol. 8 (1994) 1–13. [PMID: 7527117]
6.  Schiavo, G. and Montecucco, C. Tetanus and botulism neurotoxins. Methods Enzymol. 248 (1995) 643–652. [PMID: 7674951]
[EC created 1995]