The Enzyme Database

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EC 2.3.2.27     
Accepted name: RING-type E3 ubiquitin transferase
Reaction: [E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-N6-ubiquitinyl-L-lysine
Glossary: RING = Really Interesting New Gene
Other name(s): RING E3 ligase (misleading); ubiquitin transferase RING E3; S-ubiquitinyl-[ubiquitin-conjugating E2 enzyme]-L-cysteine:acceptor protein ubiquitin transferase (isopeptide bond-forming, RING-type)
Systematic name: [E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine:[acceptor protein] ubiquitin transferase (isopeptide bond-forming; RING-type)
Comments: RING E3 ubiquitin transferases serve as mediators bringing the ubiquitin-charged E2 ubiquitin-conjugating enzyme (EC 2.3.2.23) and an acceptor protein together to enable the direct transfer of ubiquitin through the formation of an isopeptide bond between the C-terminal glycine residue of ubiquitin and the ε-amino group of an L-lysine residue of the acceptor protein. Unlike EC 2.3.2.26, HECT-type E3 ubiquitin transferase, the RING-E3 domain does not form a catalytic thioester intermediate with ubiquitin. Many members of the RING-type E3 ubiquitin transferase family are not able to bind a substrate directly, and form a complex with a cullin scaffold protein and a substrate recognition module (the complexes are named CRL for Cullin-RING-Ligase). In these complexes, the RING-type E3 ubiquitin transferase provides an additional function, mediating the transfer of a NEDD8 protein from a dedicated E2 carrier to the cullin protein (see EC 2.3.2.32, cullin-RING-type E3 NEDD8 transferase). cf. EC 2.3.2.31, RBR-type E3 ubiquitin transferase.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, PDB
References:
1.  Eisele, F. and Wolf, D.H. Degradation of misfolded protein in the cytoplasm is mediated by the ubiquitin ligase Ubr1. FEBS Lett. 582 (2008) 4143–4146. [DOI] [PMID: 19041308]
2.  Metzger, M.B., Hristova, V.A. and Weissman, A.M. HECT and RING finger families of E3 ubiquitin ligases at a glance. J. Cell Sci. 125 (2012) 531–537. [DOI] [PMID: 22389392]
3.  Plechanovova, A., Jaffray, E.G., Tatham, M.H., Naismith, J.H. and Hay, R.T. Structure of a RING E3 ligase and ubiquitin-loaded E2 primed for catalysis. Nature 489 (2012) 115–120. [DOI] [PMID: 22842904]
4.  Pruneda, J.N., Littlefield, P.J., Soss, S.E., Nordquist, K.A., Chazin, W.J., Brzovic, P.S. and Klevit, R.E. Structure of an E3:E2~Ub complex reveals an allosteric mechanism shared among RING/U-box ligases. Mol. Cell 47 (2012) 933–942. [DOI] [PMID: 22885007]
5.  Metzger, M.B., Pruneda, J.N., Klevit, R.E. and Weissman, A.M. RING -type E3 ligases: master manipulators of E2 ubiquitin-conjugating enzymes and ubiquitination. Biochim. Biophys. Acta 1843 (2014) 47–60. [DOI] [PMID: 23747565]
[EC 2.3.2.27 created 2015, modified 2017]
 
 
EC 2.3.2.31     
Accepted name: RBR-type E3 ubiquitin transferase
Reaction: [E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-N6-ubiquitinyl-L-lysine (overall reaction)
(1a) [E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine + [RBR-type E3 ubiquitin transferase]-L-cysteine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + [RBR-type E3 ubiquitin transferase]-S-ubiquitinyl-L-cysteine
(1b) [RBR-type E3 ubiquitin transferase]-S-ubiquitinyl-L-cysteine + [acceptor protein]-L-lysine = [RBR-type E3 ubiquitin transferase]-L-cysteine + [acceptor protein]-N6-ubiquitinyl-L-lysine
Glossary: RBR = RING between RING
RING = Really Interesting New Gene
Systematic name: [E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine:acceptor protein ubiquitin transferase (isopeptide bond-forming; RBR-type)
Comments: RBR-type E3 ubiquitin transferases have two RING fingers separated by an internal motif (IBR, for In Between RING). The enzyme interacts with the CRL (Cullin-RING ubiquitin Ligase) complexes formed by certain RING-type E3 ubiquitin transferase (see EC 2.3.2.27), which include a neddylated cullin scaffold protein and a substrate recognition module. The RING1 domain binds an EC 2.3.2.23, E2 ubiquitin-conjugating enzyme, and transfers the ubiquitin that is bound to it to an internal cysteine residue in the RING2 domain, followed by the transfer of the ubiquitin from RING2 to the substrate [4]. Once the substrate has been ubiquitylated by the RBR-type ligase, it can be ubiqutylated further using ubiquitin carried directly on E2 enzymes, in a reaction catalysed by EC 2.3.2.27. Activity of the RBR-type enzyme is dependent on neddylation of the cullin protein in the CRL complex [2,4]. cf. EC 2.3.2.26, HECT-type E3 ubiquitin transferase, EC 2.3.2.27, RING-type E3 ubiquitin transferase, and EC 2.3.2.32, cullin-RING-type E3 NEDD8 transferase.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, PDB
References:
1.  Wenzel, D.M., Lissounov, A., Brzovic, P.S. and Klevit, R.E. UBCH7 reactivity profile reveals parkin and HHARI to be RING/HECT hybrids. Nature 474 (2011) 105–108. [DOI] [PMID: 21532592]
2.  Kelsall, I.R., Duda, D.M., Olszewski, J.L., Hofmann, K., Knebel, A., Langevin, F., Wood, N., Wightman, M., Schulman, B.A. and Alpi, A.F. TRIAD1 and HHARI bind to and are activated by distinct neddylated Cullin-RING ligase complexes. EMBO J. 32 (2013) 2848–2860. [DOI] [PMID: 24076655]
3.  Duda, D.M., Olszewski, J.L., Schuermann, J.P., Kurinov, I., Miller, D.J., Nourse, A., Alpi, A.F. and Schulman, B.A. Structure of HHARI, a RING-IBR-RING ubiquitin ligase: autoinhibition of an Ariadne-family E3 and insights into ligation mechanism. Structure 21 (2013) 1030–1041. [DOI] [PMID: 23707686]
4.  Scott, D.C., Rhee, D.Y., Duda, D.M., Kelsall, I.R., Olszewski, J.L., Paulo, J.A., de Jong, A., Ovaa, H., Alpi, A.F., Harper, J.W. and Schulman, B.A. Two distinct types of E3 ligases work in unison to regulate substrate ubiquitylation. Cell 166 (2016) 1198–1214.e24. [DOI] [PMID: 27565346]
[EC 2.3.2.31 created 2017]
 
 
EC 2.3.2.32     
Accepted name: cullin-RING-type E3 NEDD8 transferase
Reaction: [E2 NEDD8-conjugating enzyme]-S-[NEDD8-protein]-yl-L-cysteine + [cullin]-L-lysine = [E2 NEDD8-conjugating enzyme]-L-cysteine + [cullin]-N6-[NEDD8-protein]-yl-L-lysine
Glossary: NEDD = Neural-precursor-cell Expressed Developmentally Down-regulated protein
Other name(s): RBX1 (gene name)
Systematic name: [E2 NEDD8-conjugating enzyme]-S-[NEDD8-protein]-yl-L-cysteine:[cullin] [NEDD8-protein] transferase (isopeptide bond-forming; RING-type)
Comments: Some RING-type E3 ubiquitin transferase (EC 2.3.2.27) are not able to bind a substrate protein directly. Instead, they form a complex with a cullin scaffold protein and a substrate recognition module, which is named CRL for Cullin-RING-Ligase. The cullin protein needs to be activated by the ubiquitin-like protein NEDD8 in a process known as neddylation. The transfer of NEDD8 from a NEDD8-specific E2 enzyme onto the cullin protein is a secondary function of the RING-type E3 ubiquitin transferase in the CRL complex. The process requires auxiliary factors that belong to the DCN1 (defective in cullin neddylation 1) family.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, PDB
References:
1.  Kim, A.Y., Bommelje, C.C., Lee, B.E., Yonekawa, Y., Choi, L., Morris, L.G., Huang, G., Kaufman, A., Ryan, R.J., Hao, B., Ramanathan, Y. and Singh, B. SCCRO (DCUN1D1) is an essential component of the E3 complex for neddylation. J. Biol. Chem. 283 (2008) 33211–33220. [DOI] [PMID: 18826954]
2.  Kurz, T., Chou, Y.C., Willems, A.R., Meyer-Schaller, N., Hecht, M.L., Tyers, M., Peter, M. and Sicheri, F. Dcn1 functions as a scaffold-type E3 ligase for cullin neddylation. Mol. Cell 29 (2008) 23–35. [DOI] [PMID: 18206966]
3.  Scott, D.C., Monda, J.K., Grace, C.R., Duda, D.M., Kriwacki, R.W., Kurz, T. and Schulman, B.A. A dual E3 mechanism for Rub1 ligation to Cdc53. Mol. Cell 39 (2010) 784–796. [DOI] [PMID: 20832729]
4.  Scott, D.C., Sviderskiy, V.O., Monda, J.K., Lydeard, J.R., Cho, S.E., Harper, J.W. and Schulman, B.A. Structure of a RING E3 trapped in action reveals ligation mechanism for the ubiquitin-like protein NEDD8. Cell 157 (2014) 1671–1684. [DOI] [PMID: 24949976]
5.  Monda, J.K., Scott, D.C., Miller, D.J., Lydeard, J., King, D., Harper, J.W., Bennett, E.J. and Schulman, B.A. Structural conservation of distinctive N-terminal acetylation-dependent interactions across a family of mammalian NEDD8 ligation enzymes. Structure 21 (2013) 42–53. [DOI] [PMID: 23201271]
[EC 2.3.2.32 created 2017]
 
 
EC 2.3.2.34     
Accepted name: E2 NEDD8-conjugating enzyme
Reaction: [E1 NEDD8-activating enzyme]-S-[NEDD8 protein]-yl-L-cysteine + [E2 NEDD8-conjugating enzyme]-L-cysteine = [E1 NEDD8-activating enzyme]-L-cysteine + [E2 NEDD8-conjugating enzyme]-S-[NEDD8-protein]-yl-L-cysteine
Glossary: NEDD = Neural-precursor-cell Expressed Developmentally Down-regulated protein
Other name(s): NEDD8-carrier-protein E2; NEDD8-conjugating enzyme E2; UBE2M (gene name); UBE2F (gene name)
Systematic name: [E1 NEDD8-activating enzyme]-S-[NEDD8 protein]-yl-L-cysteine:[E2 NEDD8-conjugating enzyme] [NEDD8-protein]-yl transferase
Comments: Some RING-type E3 ubiquitin transferases (EC 2.3.2.27) are not able to bind a substrate protein directly. Instead, they form complexes with a cullin scaffold protein and a substrate recognition module, which are known as CRL (Cullin-RING-Ligase) complexes. The cullin protein needs to be activated by the ubiquitin-like protein NEDD8 in a process known as neddylation. Like ubiquitin, the NEDD8 protein ends with two glycine residues. EC 6.2.1.64, E1 NEDD8-activating enzyme, activates NEDD8 in an ATP-dependent reaction by forming a high-energy thioester intermediate between NEDD8 and one of its cysteine residues. The activated NEDD8 is subsequently transferred to a cysteine residue of an E2 NEDD8-conjugating enzyme, and is eventually conjugated to a lysine residue of specific substrates in the presence of the appropriate E3 transferase (EC 2.3.2.32, cullin-RING-type E3 NEDD8 transferase).
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, PDB
References:
1.  Osaka, F., Kawasaki, H., Aida, N., Saeki, M., Chiba, T., Kawashima, S., Tanaka, K. and Kato, S. A new NEDD8-ligating system for cullin-4A. Genes Dev. 12 (1998) 2263–2268. [PMID: 9694792]
2.  Gong, L. and Yeh, E.T. Identification of the activating and conjugating enzymes of the NEDD8 conjugation pathway. J. Biol. Chem. 274 (1999) 12036–12042. [PMID: 10207026]
3.  Huang, D.T., Miller, D.W., Mathew, R., Cassell, R., Holton, J.M., Roussel, M.F. and Schulman, B.A. A unique E1-E2 interaction required for optimal conjugation of the ubiquitin-like protein NEDD8. Nat. Struct. Mol. Biol. 11 (2004) 927–935. [PMID: 15361859]
4.  Huang, D.T., Ayrault, O., Hunt, H.W., Taherbhoy, A.M., Duda, D.M., Scott, D.C., Borg, L.A., Neale, G., Murray, P.J., Roussel, M.F. and Schulman, B.A. E2-RING expansion of the NEDD8 cascade confers specificity to cullin modification. Mol. Cell 33 (2009) 483–495. [PMID: 19250909]
[EC 2.3.2.34 created 2020]
 
 
EC 3.2.2.29     
Accepted name: thymine-DNA glycosylase
Reaction: Hydrolyses mismatched double-stranded DNA and polynucleotides, releasing free thymine.
Other name(s): mismatch-specific thymine-DNA glycosylase; mismatch-specific thymine-DNA N-glycosylase; hTDG; hsTDG; TDG; thymine DNA glycosylase; G/T glycosylase; uracil/thymine DNA glycosylase; T:G mismatch-specific thymidine-DNA glycosylase; G:T mismatch-specific thymine DNA-glycosylase
Systematic name: thymine-DNA deoxyribohydrolase (thymine-releasing)
Comments: Thymine-DNA glycosylase is part of the DNA-repair machinery. Thymine removal is fastest when it is from a G/T mismatch with a 5′-flanking C/G pair. The glycosylase removes uracil from G/U, C/U, and T/U base pairs faster than it removes thymine from G/T [3].
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, PDB
References:
1.  Waters, T.R. and Swann, P.F. Thymine-DNA glycosylase and G to A transition mutations at CpG sites. Mutat. Res. 462 (2000) 137–147. [DOI] [PMID: 10767625]
2.  Neddermann, P. and Jiricny, J. The purification of a mismatch-specific thymine-DNA glycosylase from HeLa cells. J. Biol. Chem. 268 (1993) 21218–21224. [PMID: 8407958]
3.  Waters, T.R. and Swann, P.F. Kinetics of the action of thymine DNA glycosylase. J. Biol. Chem. 273 (1998) 20007–20014. [DOI] [PMID: 9685338]
[EC 3.2.2.29 created 2009]
 
 
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, PDB, 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 6.2.1.64     
Accepted name: E1 NEDD8-activating enzyme
Reaction: ATP + [NEDD8 protein] + [E1 NEDD8-activating enzyme]-L-cysteine = AMP + diphosphate + [E1 NEDD8-activating enzyme]-S-[NEDD8 protein]-yl-L-cysteine
Glossary: NEDD = Neural-precursor-cell Expressed Developmentally Down-regulated protein
Other name(s): NEDD-activating enzyme E1; NAE1 (gene name); UBA3 (gene name)
Systematic name: [NEDD8 protein]:[E1 NEDD8-activating enzyme] ligase (AMP-forming)
Comments: Some RING-type E3 ubiquitin transferase (EC 2.3.2.27) are not able to bind a substrate protein directly. Instead, they form complexes with a cullin scaffold protein and a substrate recognition module, which are known as CRL (Cullin-RING-Ligase) complexes. The cullin protein needs to be activated by the ubiquitin-like protein NEDD8 in a process known as neddylation. Like ubiquitin, the NEDD8 protein ends with two glycine residues. The E1 NEDD8-activating enzyme activates NEDD8 in an ATP-dependent reaction by forming a high-energy thioester intermediate between NEDD8 and one of its cysteine residues. The activated NEDD8 is subsequently transferred to a cysteine residue of EC 2.3.2.34, E2 NEDD8-conjugating enzyme, and is eventually conjugated to a lysine residue of specific substrates in the presence of the appropriate E3 transferase (EC 2.3.2.32, cullin-RING-type E3 NEDD8 transferase).
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, PDB
References:
1.  Osaka, F., Kawasaki, H., Aida, N., Saeki, M., Chiba, T., Kawashima, S., Tanaka, K. and Kato, S. A new NEDD8-ligating system for cullin-4A. Genes Dev. 12 (1998) 2263–2268. [PMID: 9694792]
2.  Gong, L. and Yeh, E.T. Identification of the activating and conjugating enzymes of the NEDD8 conjugation pathway. J. Biol. Chem. 274 (1999) 12036–12042. [PMID: 10207026]
[EC 6.2.1.64 created 2020]
 
 


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