Ser- and -AlaAla- bonds in the scaffold proteinEnzyme Nomenclature. Recommendations 1992
Prepared on behalf of the advisory panel on peptidase nomenclature by Alan J. BARRETT, The Babraham Institute, Cambridge CB2 4AT, England
This document contains further additions and amendments to Enzyme Nomenclature 1992, published by Academic Press, Orlando, Florida. Supplements 1, 2, 3, 4 and 5 were published in Eur. J. Biochem. 223 (1994) 1-5 , Eur. J. Biochem. 232 (1995) 1-6 , Eur. J. Biochem. 237 (1996) 1-5 , Eur. J. Biochem. 250 (1997) 1-6 and Eur. J. Biochem. 264 (1999) 610-650 . An entry marked with an asterisk is a revision of a pre-existing entry. Families of peptidases are referred to by use of the numbering system of Rawlings and Barrett (Methods Enzymol. 244 (1994) 19-61 and 461-486; Methods Enzymol. 248 (1995) 105-120 and 183-228; MEROPS database at http://www.merops.co.uk/). The full, amended text of subclass EC 3.4 (peptidases) of Enzyme Nomenclature 1992 may be found on the Internet at http://www.qmul.ac.uk/iubmb/enzyme/EC34/. Comments and suggestions on enzyme classification and nomenclature may be sent to Prof. K. F. Tipton, Department of Biochemistry, Trinity College Dublin, Dublin 2, Ireland. These changes were approved at the meeting of NC-IUBMB held May 2000.
Recommended name: aspartyl aminopeptidase
Reaction: release of an N-terminal aspartate or glutamate from a peptide, with a preference for aspartate
Comments: Aminoacyl-arylamides are poor substrates. This is an abundant cytosolic enzyme in mammalian cells, in peptidase family M18 of aminopeptidase I
References:
1. Kelly, J.A., Neidle, E.L. and Neidle, A. An aminopeptidase from mouse brain cytosol that cleaves N-terminal acidic amino acid residues. J. Neurochem. 40 (1983) 1727-1734. [Medline UI: 83215350]
2. Wilk, S., Wilk, E. and Magnusson, R.P. Purification, characterization and cloning of a cytosolic aspartyl aminopeptidase. J. Biol. Chem. 273 (1998) 15961-15970. [Medline UI: 98298097]
[EC 3.4.13.8 Transferred entry: now EC 3.4.13.18 - cytosol nonspecific dipeptidase]
Recommended name: cytosol nonspecific dipeptidase
Reaction: hydrolysis of dipeptides, preferentially hydrophobic dipeptides including prolyl amino acids
Other Names: N2-β-alanylarginine dipeptidase; glycyl-glycine dipeptidase; glycyl-leucine dipeptidase; iminodipeptidase; peptidase A; Pro-X dipeptidase; prolinase; prolyl dipeptidase; prolylglycine dipeptidase
Comments: A zinc enzyme with broad specificity varying somewhat with source species. Activated and stabilized by dithiothreitol and Mn2+. Inhibited by bestatin and leucine. Formerly EC 3.4.3.1, 3.4.3.2, 3.4.3.6, 3.4.13.1, 3.4.13.2, 3.4.13.8, 3.4.13.11 and 3.4.13.15
References:
1. Bauer, K. Cytosol non-specific dipeptidase. In: Handbook of Proteolytic Enzymes (Barrett, A. J., Rawlings, N. D. and Woessner, J. F., eds), (1998) pp. 1520-1522, Academic Press, London
Recommended name: glutamate carboxypeptidase II
Reaction: release of an unsubstituted, C-terminal glutamyl residue, typically from Ac-Asp-Glu or folylpoly-γ-glutamates
Other names: N-acetylated-γ-linked-acidic dipeptidase (NAALADase); folate hydrolase; prostate-specific membrane antigen; pteroylpoly-γ-glutamate carboxypeptidase
Comments: A metallo-carboxypeptidase that is predominantly expressed as a membrane-bound enzyme of 94-100 kDa , but also exists in a soluble form. Hydrolyses γ-peptide bonds in Ac-Asp-Glu, Asp-Glu, and Glu-Glu, but also γ-glutamyl bonds in γ-Glu-Glu and folylpoly-γ-glutamates. With folylpoly-γ-glutamates, shows processive carboxypeptidase activity to produce pteroylmonoglutamate [4]. Does not hydrolyse Ac-γ-Asp-Glu. Known inhibitors: quisqualic acid, Ac-γ-Asp-Glu, and 2-phosphonomethyl-pentanedioate. In peptidase family M28 of Vibrio leucyl aminopeptidase. Formerly EC 3.4.19.8. The release of C-terminal glutamate from folylpoly-γ-glutamates is also catalysed by glutamate carboxypeptidase (EC 3.4.17.11) and γ-Glu-X carboxypeptidase (EC 3.4.19.9)
References:
1. Heston, W.D.W. Characterization and glutamyl preferring carboxypeptidase function of prostate specific membrane antigen: a novel folate hydrolase. Urology 49 (1997) 104-112. [Medline UI: 97237008]
2. Rawlings, N.D. and Barrett, A.J. Structure of membrane glutamate carboxypeptidase. Biochim. Biophys. Acta 1339 (1997) 247-252. [Medline UI: 97330810]
3. Halsted, C.H., Ling, E.-H., Luthi-Carter, R., Villanueva, J.A., Gardner, J.M., and Coyle, J.T. Folylpoly-γ-glutamate carboxypeptidase from pig jejunum: molecular characterization and relation to glutamate carboxypeptidase II. J. Biol. Chem. 273 (1998) 20417-20424. [Medline UI: 98352082]
4. Luthi-Carter, R., Berger, U.V., Barczak, A.K., Enna, M. and Coyle, J.T. Isolation and expression of a rat brain cDNA encoding glutamate carboxypeptidase II. Proc. Natl Acad. Sci. USA 95 (1998) 3215-3220. [Medline UI: 98169524]
[EC 3.4.19.8 Transferred entry: now EC 3.4.17.21 - glutamate carboxypeptidase II]
Recommended name: ubiquitinyl hydrolase 1
Reaction: thiol-dependent hydrolysis of ester, thiolester, amide, peptide and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-residue protein attached to proteins as an intracellular targeting signal)
Other names: ubiquitin C-terminal hydrolase; yeast ubiquitin hydrolase
Comments: Links to polypeptides smaller than 60 residues are hydrolysed more readily than those to larger polypeptides. Isoforms exist with quantitatively different specificities amongst the best known being UCH-L1 and UCH-L3, major proteins of the brain of mammals [1]. Inhibited by ubiquitin aldehyde (in which Gly76 is replaced by aminoacetaldehyde). Ubiquitinyl hydrolase 1 is the type example of peptidase family C12, with a similar protein fold to papain and catalytic amino acids Cys, His and Asp. There is a separate family (C19) of enzymes that also hydrolyse ubiquitinyl bonds, and it is thought that all the ubiquitinyl hydrolases are also ubiquitin thiolesterases (EC 3.1.2.15)
References:
1. Johnston, S.C., Larsen, C.N., Cook, W.J., Wilkinson, K.D. and Hill, C.P. Crystal structure of a deubiquitinating enzyme (human UCH-L3) at 1.8Å resolution. EMBO J. 16 (1997) 3787-3796. [Medline UI: 97377017]
2. Wilkinson, K.D. Ubiquitin C-terminal hydrolase. In: Handbook of Proteolytic Enzymes (Barrett, A.J., Rawlings, N.D. and Woessner, J.F. eds), (1998) pp. 660-663, Academic Press, London
Recommended name: assemblin
Reaction: cleaves -AlaSer- and -AlaAla- 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
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) 835-843. [Medline UI: 96390856]
2. Darke, P.L. Herpesvirus assemblin. In: Handbook of Proteolytic Enzymes, (Barrett, A.J., Rawlings, N.D. and Woessner, J.F. eds), (1998) pp. 470-472, Academic Press, London
Recommended 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 names: 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
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. [Medline UI: 97015089]
2. Rice, C.M. Hepatitis C virus polyprotein peptidase. In: Handbook of Proteolytic Enzymes (Barrett, A.J., Rawlings, N.D. and Woessner, J.F. eds), (1998) pp. 272-277, Academic Press, London
Recommended name: papain
Reaction: hydrolysis of proteins with broad specificity for peptide bonds, but preference for an amino acid bearing a large hydrophobic side chain in the P2 position. Does not accept Val in P1'
Comments: Type example of peptidase family C1 from latex of the papaya fruit (Carica papaya). Inhibited by compound E-64 and proteins of the cystatin family. Formerly EC 3.4.4.10
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. [Medline UI: 85210914]
2. Ménard, R. and Storer, A.C. Papain. In: Handbook of Proteolytic Enzymes, Barrett, A.J., Rawlings, N.D. and Woessner, J.F. eds), (1998) p.555-557, Academic Press, London.
Recommended name: legumain
Reaction: hydrolysis of proteins and small-molecule substrates at -AsnXaa-bonds
Other Names: asparaginyl endopeptidase; citvac; proteinase B (ambiguous); hemoglobinase (ambiguous); phaseolin; PRSC1 gene product (Homo sapiens); vicilin peptidohydrolase
Comments: Best known from legume seeds, the trematode Schistosoma mansoni and mammalian lysosomes. Not inhibited by compound E-64. Type example of peptidase family C13
References:
1. Hara-Nishimura, I. Asparaginyl endopeptidase. In: Handbook of Proteolytic Enzymes (Barrett, A.J., Rawlings, N.D. and Woessner, J.F. eds), (1998) pp. 746-749, Academic Press, London
2. Dalton, J.P. and Brindley, P.J. Schistosome legumain. In: Handbook of Proteolytic Enzymes (Barrett, A.J., Rawlings, N.D. and Woessner, J.F. eds), (1998) pp. 749-754, Academic Press, London
3. Chen, J.-M., Rawlings, N.D., Stevens, R.A.E. and Barrett, A.J. Identification of the active site of legumain links it to caspases, clostripain and gingipains in a new clan of cysteine endopeptidases. FEBS Letters 441 (1998) 361-365. [Medline UI: 99106989]
Recommended name: adenain
Reaction: cleaves proteins of the adenovirus and its host cell at two consensus sites: -Yaa-Xaa-Gly-GlyXaa- and -Yaa-Xaa-Gly-XaaGly- (in which Yaa is Met, Ile or Leu, and Xaa is any amino acid)
Comments: A cysteine endopeptidase from adenoviruses, the type example of 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]
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. [Medline UI: 93137333]
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. [Medline UI: 96203097]
3. Weber, J.M. Adenovirus protease. In: Handbook of Proteolytic Enzymes (Barrett, A.J., Rawlings, N.D. and Woessner, J.F. eds), (1998) pp. 741-743, Academic Press, London
Recommended name: bleomycin hydrolase
Reaction: inactivates bleomycin B2 (a cytotoxic glycometallopeptide) by hydrolysis of a carboxyamide bond of β-aminoalanine, but also shows general aminopeptidase activity. The specificity varies somewhat with source, but amino acid arylamides of Met, Leu and Ala are preferred [1]
Other names: aminopeptidase C (Lactococcus lactis) [4]
Comment: The molecule is a homohexamer in which the monomers have a papain-like tertiary structure (in peptidase family C1). The active sites are on the walls of a central channel through the molecule, and access of substrate molecules to them is obstructed by this and by the C-terminus of each polypeptide chain [3]. Bleomycin can scarcely be the natural substrate, and there are reports of limited endopeptidase activity. Known from bacteria as well as eukaryotic organisms. Hydrolase H from chicken muscle has many similarities to bleomycin hydrolase, but hydrolyses Ph-CO-Arg-2-naphthylamine as well as aminopeptidase substrates [2]
References:
1. Brömme, D., Rossi, A.B., Smeekens, S.P., Anderson, D.C. and Payan, D.G. Human bleomycin hydrolase: molecular cloning, sequencing, functional expression, and enzymatic characterization. Biochemistry 35 (1996) 6706-6714. [Medline UI: 96234975]
2. Adachi, H., Tsujimoto, M., Fukasawa, M., Sato, Y., Arai, H., Inoue, K. and Nishimura, T. cDNA cloning and expression of chicken aminopeptidase H, possessing endopeptidase as well as aminopeptidase activity. Eur. J. Biochem. 245 (1997) 283-288. [Medline UI: 97296390]
3. Zheng, W., Johnston, S.A. and Joshua-Tor, L. The unusual active site of Gal6/bleomycin hydrolase can act as a carboxypeptidase, aminopeptidase, and peptide ligase. Cell 93 (1998) 103-109. [Medline UI: 98206472]
4. Mistou, M.Y. and Gripon, J.C. Catalytic properties of the cysteine aminopeptidase PepC, a bacterial bleomycin hydrolase. Biochim. Biophys. Acta 1383 (1998) 63-70. [Medline UI: 98207691]
Recommended name: HIV-1 retropepsin
Reaction: specific for a P1 residue that is hydrophobic, and P1' variable, but often Pro
Other names: human immunodeficiency virus type 1 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
References:
1. Kuo, L.C. and Schafer, J.A. (eds) Methods in Enzymology. 241. (1994) Retroviral Proteases.
2. Dunn, B.M. Human immunodeficiency virus 1 retropepsin. In: Handbook of Proteolytic Enzymes (Barrett, A.J., Rawlings, N.D. and Woessner, J.F. eds), (1998) pp.919-928, Academic Press, London
Recommended 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 names: 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]
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. [Medline UI: 96223990]
2. Fuller, R.S. Yapsin 2. In: Handbook of Proteolytic Enzymes, Barrett, A.J., Rawlings, N.D. and Woessner, J.F. eds), (1998) pp. 908-909, Academic Press, London
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. [Medline UI: 98153160]
Recommended name: thermopsin
Reaction: similar in specificity to pepsin A preferring bulky hydrophobic amino acids in P1 and P1'
Comments: From the thermophilic archeaon Sulfolobus acidocaldarius. Maximally active at pH 2 and 90 °C. Weakly inhibited by pepstatin but shows no sequence similarity to pepsin. Type example of peptidase family A5. Formerly EC 3.4.99.44
References:
1. Lin, X. and Tang, J. Thermopsin. Methods Enzymol. 248 (1995) 156-168. [Medline UI: 95405258]
Recommended name: gametolysin
Reaction: cleavage of the proline- and hydroxyproline-rich proteins of the Chlamydomonas reinhardtii cell wall; also cleaves azocasein, gelatin and Leu-Trp-MetArg-Phe-Ala
Other Names: autolysin; chlamydomonas cell wall degrading protease; lysin
Comments: A glycoprotein found in the periplasmic space of C. 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
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. [Medline UI: 88082858]
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. [Medline UI: 89093232]
3. Matsuda, Y. Gametolysin. In: Handbook of Proteolytic Enzymes (Barrett, A.J., Rawlings, N.D. and Woessner, J.F. eds), (1998) pp. 1140-1143, Academic Press, London
Recommended name: flavastacin
Reaction: hydrolyses polypeptides on the amino-side of Asp in -XaaAsp-. Acts very slowly on -XaaGlu
Comments: A zinc metalloendopeptidase in peptidase family M12 of astacin, secreted by the bacterium Flavobacterium meningosepticum. The specificity is similar to that of peptidyl-Asp metalloendopeptidase from Pseudomonas fragi (EC 3.4.24.33), but the two are reported to be structurally dissimilar
References:
1. Tarentino, A.L., Quinones, G., Grimwood, B.G., Hauer, C.R. and Plummer, T.H., Jr. Molecular cloning and sequence analysis of flavastacin: an O-glycosylated prokaryotic zinc metalloendopeptidase. Arch. Biochem. Biophys. 319 (1995) 281-285. [Medline UI: 95286605]
EC 3.4.25 Threonine Endopeptidases
Recommended name: proteasome endopeptidase complex
Reaction: cleavage of peptide bonds with very broad specificity
Other Names: ingensin; macropain; multicatalytic endopeptidase complex; prosome
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 two of the 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. Formerly EC 3.4.24.5, 3.4.22.21 and 3.4.99.46
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. [Medline UI: 95242106]
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. [Medline UI: 96407109]
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. [Medline UI: 97242404]
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. [Medline UI: 98421476]
[EC 3.4.99.43 Transferred entry: now EC 3.4.23.42 - thermopsin]
[EC 3.4.99.46 Transferred entry: now EC 3.4.25.1 - proteasome endopeptidase complex]