of glycoprotein gp43 in Xenopus laevis coelemic egg envelope to yield gp41
An asterisk before 'EC' indicates that this is an amendment to an existing enzyme rather than a new enzyme entry.
Accepted name: 1,5-anhydro-D-fructose reductase (1,5-anhydro-D-mannitol-forming)
Reaction: 1,5-anhydro-D-mannitol + NADP+ = 1,5-anhydro-D-fructose + NADPH + H+
For diagram click here.
Other name(s): 1,5-anhydro-D-fructose reductase (ambiguous); AFR
Systematic name: 1,5-anhydro-D-mannitol:NADP+ oxidoreductase
Comments: This enzyme is present in some but not all Rhizobium species and belongs in the GFO/IDH/MocA protein family [2]. This enzyme differs from hepatic 1,5-anhydro-D-fructose reductase, which yields 1,5-anhydro-D-glucitol as the product (see EC 1.1.1.263). In Sinorhizobium morelense, the product of the reaction, 1,5-anhydro-D-mannitol, can be further metabolized to D-mannose [1]. The enzyme also reduces 1,5-anhydro-D-erythro-hexo-2,3-diulose and 2-ketoaldoses (called osones), such as D-glucosone (D-arabino-hexos-2-ulose) and 6-deoxy-D-glucosone. It does not reduce common aldoses and ketoses, or non-sugar aldehydes and ketones [1].
References:
1. Kühn, A., Yu, S. and Giffhorn, F. Catabolism of 1,5-anhydro-D-fructose in Sinorhizobium morelense S-30.7.5: discovery, characterization, and overexpression of a new 1,5-anhydro-D-fructose reductase and its application in sugar analysis and rare sugar synthesis. Appl. Environ. Microbiol. 72 (2006) 1248-1257. [PMID: 16461673]
2. Dambe, T.R., Kühn, A.M., Brossette, T., Giffhorn, F. and Scheidig, A.J. Crystal structure of NADP(H)-dependent 1,5-anhydro-D-fructose reductase from Sinorhizobium morelense at 2.2 Å resolution: construction of a NADH-accepting mutant and its application in rare sugar synthesis. Biochemistry 45 (2006) 10030-10042. [PMID: 16906761]
Accepted name: 7-methylxanthosine synthase
Reaction: S-adenosyl-L-methionine + xanthosine = S-adenosyl-L-homocysteine + 7-methylxanthosine
For diagram of reaction click here
Other name(s): xanthosine methyltransferase; XMT; xanthosine:S-adenosyl-L-methionine methyltransferase; CtCS1; CmXRS1; CaXMT1; CmXRS1; S-adenosyl-L-methionine:xanthosine 7-N-methyltransferase
Systematic name: S-adenosyl-L-methionine:xanthosine N7-methyltransferase
Comments: The enzyme is specific for xanthosine, as XMP and xanthine cannot act as substrates [2,4]. The enzyme does not have N1- or N3- methylation activity [2]. This is the first methylation step in the production of caffeine.
References:
1. Negishi, O., Ozawa, T. and Imagawa, H. The role of xanthosine in the biosynthesis of caffeine in coffee plants. Agric. Biol. Chem. 49 (1985) 2221-2222.
2. Mizuno, K., Kato, M., Irino, F., Yoneyama, N., Fujimura, T. and Ashihara, H. The first committed step reaction of caffeine biosynthesis: 7-methylxanthosine synthase is closely homologous to caffeine synthases in coffee (Coffea arabica L.). FEBS Lett. 547 (2003) 56-60. [PMID: 12860386]
3. Uefuji, H., Ogita, S., Yamaguchi, Y., Koizumi, N. and Sano, H. Molecular cloning and functional characterization of three distinct N-methyltransferases involved in the caffeine biosynthetic pathway in coffee plants. Plant Physiol. 132 (2003) 372-380. [PMID: 12746542]
4. Yoneyama, N., Morimoto, H., Ye, C.X., Ashihara, H., Mizuno, K. and Kato, M. Substrate specificity of N-methyltransferase involved in purine alkaloids synthesis is dependent upon one amino acid residue of the enzyme. Mol. Genet. Genomics 275 (2006) 125-135. [PMID: 16333668]
Accepted name: theobromine synthase
Reaction: S-adenosyl-L-methionine + 7-methylxanthine = S-adenosyl-L-homocysteine + 3,7-dimethylxanthine
For diagram of reaction click here
Glossary: theobromine = 3,7-dimethylxanthine
paraxanthine = 1,7-dimethylxanthine
Other name(s): monomethylxanthine methyltransferase; MXMT; CTS1; CTS2; S-adenosyl-L-methionine:7-methylxanthine 3-N-methyltransferase
Systematic name: S-adenosyl-L-methionine:7-methylxanthine N3-methyltransferase
Comments: This is the third enzyme in the caffeine-biosynthesis pathway. This enzyme can also catalyse the conversion of paraxanthine into caffeine, although the paraxanthine pathway is considered to be a minor pathway for caffeine biosynthesis [2,3].
References:
1. Ogawa, M., Herai, Y., Koizumi, N., Kusano, T. and Sano, H. 7-Methylxanthine methyltransferase of coffee plants. Gene isolation and enzymatic properties. J. Biol. Chem. 276 (2001) 8213-8218. [PMID: 11108716]
2. Uefuji, H., Ogita, S., Yamaguchi, Y., Koizumi, N. and Sano, H. Molecular cloning and functional characterization of three distinct N-methyltransferases involved in the caffeine biosynthetic pathway in coffee plants. Plant Physiol. 132 (2003) 372-380. [PMID: 12746542]
3. Yoneyama, N., Morimoto, H., Ye, C.X., Ashihara, H., Mizuno, K. and Kato, M. Substrate specificity of N-methyltransferase involved in purine alkaloids synthesis is dependent upon one amino acid residue of the enzyme. Mol. Genet. Genomics 275 (2006) 125-135. [PMID: 16333668]
Accepted name: caffeine synthase
Reaction: (1) S-adenosyl-L-methionine + 3,7-dimethylxanthine = S-adenosyl-L-homocysteine + 1,3,7-trimethylxanthine
(2) S-adenosyl-L-methionine + 1,7-dimethylxanthine = S-adenosyl-L-homocysteine + 1,3,7-trimethylxanthine
(3) S-adenosyl-L-methionine + 7-dimethylxanthine = S-adenosyl-L-homocysteine + 3,7-dimethylxanthine
For diagram of reaction click here
Glossary: theobromine = 3,7-dimethylxanthine
paraxanthine = 1,7-dimethylxanthine
caffeine = 1,3,7-trimethylxanthine
Other name(s): dimethylxanthine methyltransferase, 3N-methyltransferase; DXMT; CCS1; S-adenosyl-L-methionine:3,7-dimethylxanthine 1-N-methyltransferase
Systematic name: S-adenosyl-L-methionine:3,7-dimethylxanthine N1-methyltransferase
Comments: Paraxanthine is the best substrate for this enzyme but the paraxanthine pathway is considered to be a minor pathway for caffeine biosynthesis [2,3].
References:
1. Kato, M., Mizuno, K., Fujimura, T., Iwama, M., Irie, M., Crozier, A. and Ashihara, H. Purification and characterization of caffeine synthase from tea leaves. Plant Physiol. 120 (1999) 579-586. [PMID: 10364410]
2. Mizuno, K., Okuda, A., Kato, M., Yoneyama, N., Tanaka, H., Ashihara, H. and Fujimura, T. Isolation of a new dual-functional caffeine synthase gene encoding an enzyme for the conversion of 7-methylxanthine to caffeine from coffee (Coffea arabica L.). FEBS Lett. 534 (2003) 75-81. [PMID: 12527364]
3. Uefuji, H., Ogita, S., Yamaguchi, Y., Koizumi, N. and Sano, H. Molecular cloning and functional characterization of three distinct N-methyltransferases involved in the caffeine biosynthetic pathway in coffee plants. Plant Physiol. 132 (2003) 372-380. [PMID: 12746542]
4. Kato, M., Mizuno, K., Crozier, A., Fujimura, T. and Ashihara, H. Caffeine synthase gene from tea leaves. Nature 406 (2000) 956-957. [PMID: 10984041]
[EC 2.4.1.112 Deleted entry: The protein referred to in this entry is now known to be glycogenin so the entry has been incorporated into EC 2.4.1.186, glycogenin glucosyltransferase (EC 2.4.1.112 created 1984, deleted 2007)]
Accepted name: glycogenin glucosyltransferase
Reaction: UDP-α-D-glucose + glycogenin = UDP + α-D-glucosylglycogenin
Other name(s): glycogenin; priming glucosyltransferase; UDP-glucose:glycogenin glucosyltransferase
Systematic name: UDP-α-D-glucose:glycogenin α-D-glucosyltransferase
Comments: The first reaction of this enzyme is to catalyse its own glucosylation, normally at Tyr-194 of the protein if this group is free. When Tyr-194 is replaced by Thr or Phe, the enzyme's Mn2+-dependent self-glucosylation activity is lost but its intermolecular transglucosylation ability remains [7]. It continues to glucosylate an existing glucosyl group until a length of about 5—13 residues has been formed. Further lengthening of the glycogen chain is then carried out by EC 2.4.1.11, glycogen (starch) synthase. The enzyme is not highly specific for the donor, using UDP-xylose in addition to UDP-glucose (although not glucosylating or xylosylating a xylosyl group so added). It can also use CDP-glucose and TDP-glucose, but not ADP-glucose or GDP-glucose. Similarly it is not highly specific for the acceptor, using water (i.e. hydrolysing UDP-glucose) among others. Various forms of the enzyme exist, and different forms predominate in different organs. Thus primate liver contains glycogenin-2, of molecular mass 66 kDa, whereas the more widespread form is glycogenin-1, with a molecular mass of 38 kDa.
Links to other databases: BRENDA, ERGO, EXPASY, KEGG, PDB, CAS registry number: 117590-73-5
References:
1. Krisman, C.R. and Barengo, R. A precursor of glycogen biosynthesis: α-1,4-glucan-protein. Eur. J. Biochem. 52 (1975) 117-123. [PMID: 809265]
2. Pitcher, J., Smythe, C., Campbell, D.G. and Cohen, P. Identification of the 38-kDa subunit of rabbit skeletal muscle glycogen synthase as glycogenin. Eur. J. Biochem. 169 (1987) 497-502. [PMID: 3121316]
3. Pitcher, J., Smythe, C. and Cohen, P. Glycogenin is the priming glucosyltransferase required for the initiation of glycogen biogenesis in rabbit skeletal muscle. Eur. J. Biochem. 176 (1988) 391-395. [PMID: 2970965]
4. Kennedy, L.D., Kirkman, B.R., Lomako, J., Rodriguez, I.R. and Whelan, W.J. The biogenesis of rabbit-muscle glycogen. In: Berman, M.C. and Opie, L.A. (Eds), Membranes and Muscle, ICSU Press/IRL Press, Oxford, 1985, pp. 65-84.
5. Rodriguez, I.R. and Whelan, W.J. A novel glycosyl-amino acid linkage: rabbit-muscle glycogen is covalently linked to a protein via tyrosine. Biochem. Biophys. Res. Commun. 132 (1985) 829-836. [PMID: 4062948]
6. Lomako, J., Lomako, W.M. and Whelan, W.J. A self-glucosylating protein is the primer for rabbit muscle glycogen biosynthesis. FASEB J. 2 (1988) 3097-3103. [PMID: 2973423]
7. Alonso, M.D., Lomako, J., Lomako, W.M. and Whelan, W.J. Catalytic activities of glycogenin additional to autocatalytic self-glucosylation. J. Biol. Chem. 270 (1995) 15315-15319. [PMID: 7797519]
8. Alonso, M.D., Lomako, J., Lomako, W.M. and Whelan, W.J. A new look at the biogenesis of glycogen. FASEB J. 9 (1995) 1126-1137. [PMID: 7672505]
9. Mu, J. and Roach, P.J. Characterization of human glycogenin-2, a self-glucosylating initiator of liver glycogen metabolism. J. Biol. Chem. 273 (1998) 34850-34856. [PMID: 9857012]
10. Gibbons, B.J., Roach, P.J. and Hurley, T.D. Crystal structure of the autocatalytic initiator of glycogen biosynthesis, glycogenin. J. Mol. Biol. 319 (2002) 463-177. [PMID: 12051921]
Accepted name: hyaluronan synthase
Reaction: (1) UDP-α-N-acetyl-D-glucosamine + β-D-glucuronosyl-(1→3)-N-acetyl-β-D-glucosaminyl-(1→4)-[nascent hyaluronan] = UDP + N-acetyl-β-D-glucosaminyl-(1→4)-β-D-glucuronosyl-(1→3)-N-acetyl-β-D-glucosaminyl-(1→4)-[nascent hyaluronan]
(2) UDP-α-D-glucuronate + N-acetyl-β-D-glucosaminyl-(1→4)-β-D-glucuronosyl-(1→3)-[nascent hyaluronan] = UDP + β-D-glucuronosyl-(1→3)-N-acetyl-β-D-glucosaminyl-(1→4)-β-D-glucuronosyl-(1→3)-[nascent hyaluronan]
For diagram click here.
Glossary: GlcNAc = N-acetyl-D-glucosamine
GlcA = glucuronic acid
Other name(s): spHAS; seHAS
Systematic name: Alternating UDP-α-N-acetyl-D-glucosamine:β-D-glucuronosyl-(1→3)-[nascent hyaluronan] 4-N-acetyl-β-D-glucosaminyltransferase and UDP-α-D-glucuronate:N-acetyl-β-D-glucosaminyl-(1→4)-[nascent hyaluronan] 3-β-D-glucuronosyltransferase
Comments: The enzyme from Streptococcus Group A and Group C requires Mg2+. The enzyme adds GlcNAc to nascent hyaluronan when the non-reducing end is GlcA, but it adds GlcA when the non-reducing end is GlcNAc [3]. The enzyme is highly specific for UDP-GlcNAc and UDP-GlcA; no copolymerization is observed if either is replaced by UDP-Glc, UDP-Gal, UDP-GalNAc or UDP-GalA. Similar enzymes have been found in a variety of organisms.
Links to other databases: BRENDA, ERGO, EXPASY, KEGG, CAS registry number:
References:
1. DeAngelis, P.L., Papaconstantinou, J. and Weigel, P.H. Molecular cloning, identification and sequence of the hyaluronan synthase gene from Group A Streptococcus pyogenes. J. Biol. Chem. 268 (1993) 19181-19184. [PMID: 8366070]
2. Jing, W. and DeAngelis, P.L. Dissection of the two transferase activities of the Pasteurella multocida hyaluronan synthase: two active sites exist in one polypeptide. Glycobiology 10 (2000) 883-889. [PMID: 10988250]
3. DeAngelis, P.L. Molecular directionality of polysaccharide polymerization by the Pasteurella multocida hyaluronan synthase. J. Biol. Chem. 274 (1999) 26557-26562. [PMID: 10473619]
Accepted name: chrysanthemyl diphosphate synthase
Reaction: 2 dimethylallyl diphosphate = diphosphate + chrysanthemyl diphosphate
For diagram of reaction click here
Other name(s): CPPase
Systematic name: dimethylallyl-diphosphate:dimethylallyl-diphosphate dimethylallyltransferase (chrysanthemyl-diphosphate-forming)
Comments: Requires a divalent metal ion for activity, with Mg2+ being better than Mn2+ [1]. Chrysanthemyl diphosphate is a monoterpenoid with a non-head-to-tail linkage. It is unlike most monoterpenoids, which are derived from geranyl diphosphate and have isoprene units that are linked head-to-tail. The mechanism of its formation is similar to that of the early steps of squalene and phytoene biosynthesis. Chrysanthemyl diphosphate is the precursor of chrysanthemic acid, the acid half of the pyrethroid insecticides found in chrysanthemums.
References:
1. Rivera, S.B., Swedlund, B.D., King, G.J., Bell, R.N., Hussey, C.E., Jr., Shattuck-Eidens, D.M., Wrobel, W.M., Peiser, G.D. and Poulter, C.D. Chrysanthemyl diphosphate synthase: isolation of the gene and characterization of the recombinant non-head-to-tail monoterpene synthase from Chrysanthemum cinerariaefolium. Proc. Natl. Acad. Sci. USA 98 (2001) 4373-4378. [PMID: 11287653]
2. Erickson, H.K. and Poulter, C.D. Chrysanthemyl diphosphate synthase. The relationship among chain elongation, branching, and cyclopropanation reactions in the isoprenoid biosynthetic pathway. J. Am. Chem. Soc. 125 (2003) 6886-6888. [PMID: 12783539]
Accepted name: Z-farnesyl diphosphate synthase
Reaction: geranyl diphosphate + isopentenyl diphosphate = diphosphate + (2Z,6E)-farnesyl diphosphate
For diagram of reaction click here
Other name(s): (Z)-farnesyl diphosphate synthase
Systematic name: geranyl-diphosphate:isopentenyl-diphosphate geranylcistransferase
Comments: Requires Mg2+ or Mn2+ for activity. The product of this reaction is an intermediate in the synthesis of decaprenyl phosphate, which plays a central role in the biosynthesis of most features of the mycobacterial cell wall, including peptidoglycan, linker unit galactan and arabinan. Neryl diphosphate can also act as substrate.
References:
1. Schulbach, M.C., Mahapatra, S., Macchia, M., Barontini, S., Papi, C., Minutolo, F., Bertini, S., Brennan, P.J. and Crick, D.C. Purification, enzymatic characterization, and inhibition of the Z-farnesyl diphosphate synthase from Mycobacterium tuberculosis. J. Biol. Chem. 276 (2001) 11624-11630. [PMID: 11152452]
Accepted name: lavandulyl diphosphate synthase
Reaction: 2 dimethylallyl diphosphate = diphosphate + lavandulyl diphosphate
For diagram of reaction click here
Other name(s): FDS-5
Systematic name: dimethylallyl-diphosphate:dimethylallyl-diphosphate dimethylallyltransferase (lavandulyl-diphosphate-forming)
Comments: Lavandulyl diphosphate is a monoterpenoid with a non-head-to-tail linkage. It is unlike most monoterpenoids, which are derived from geranyl diphosphate and have isoprene units that are linked head-to-tail. When this enzyme is incubated with dimethylallyl diphosphate and isopentenyl diphosphate, it also forms the regular monoterpene geranyl diphosphate [2]. The enzyme from Artemisia tridentata (big sagebrush) forms both lavandulyl diphosphate and chrysanthemyl diphosphate (see EC 2.5.1.67, chrysanthemyl diphosphate synthase) when dimethylally diphosphate is the sole substrate.
References:
1. Erickson, H.K. and Poulter, C.D. Chrysanthemyl diphosphate synthase. The relationship among chain elongation, branching, and cyclopropanation reactions in the isoprenoid biosynthetic pathway. J. Am. Chem. Soc. 125 (2003) 6886-6888. [PMID: 12783539]
2. Hemmerlin, A., Rivera, S.B., Erickson, H.K. and Poulter, C.D. Enzymes encoded by the farnesyl diphosphate synthase gene family in the Big Sagebrush Artemisia tridentata ssp. spiciformis. J. Biol. Chem. 278 (2003) 32132-32140. [PMID: 12782626]
Accepted name: λ-carrageenase
Reaction: Endohydrolysis of β-1,4-linkages in the backbone of λ-carrageenan, resulting in the tetrasaccharide α-D-Galp2,6S2-(1→3)-β-D-Galp2S-(1→4)-α-D-Galp2,6S2-(1→3)-D-Galp2S
For diagram click here.
Glossary: carrageenan
Other name(s): endo-β-1,4-carrageenose 2,6,2′-trisulfate-hydrolase
Comments: The enzyme from Pseudoalteromonas sp. is specific for λ-carrageenan. ι-Carrageenan (see EC 3.2.1.157, ι-carrageenase), κ-carrageenan (see EC 3.2.1.83, κ-carrageenase), agarose and porphyran are not substrates.
References:
1. Ohta, Y. and Hatada, Y. A novel enzyme, λ-carrageenase, isolated from a deep-sea bacterium. J. Biochem. (Tokyo) 140 (2006) 475-481. [PMID: 16926183]
Accepted name: N-methyl nucleosidase
Reaction: 7-methylxanthosine + H2O = 7-methylxanthine + D-ribose
For diagram of reaction click here
Other name(s): 7-methylxanthosine nucleosidase; N-MeNase; N-methyl nucleoside hydrolase; methylpurine nucleosidase
Systematic name: 7-methylxanthosine ribohydrolase
Comments: The enzyme preferentially hydrolyses 3- and 7-methylpurine nucleosides, such as 3-methylxanthosine, 3-methyladenosine and 7-methylguanosine. Hydrolysis of 7-methylxanthosine to form 7-methylxanthine is the second step in the caffeine-biosynthesis pathway.
References:
1.Negishi, O., Ozawa, T. and Imagawa, H. N-Methyl nucleosidase from tea leaves. Agric. Biol. Chem. 52 (1988) 169-175.
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 p43 to p41 by the pars recta protease oviductin. It is thought that the enzymatically 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.
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. [PMID: 11846486]
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, ERGO, EXPASY, KEGG, 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. [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 only. [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. [PMID: 9054418]
6. Martinon, F. and Tschopp, J. Inflammatory caspases: linking an intracellular innate immune system to autoinflammatory diseases. Cell 117 (2004) 561-574. [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]
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 3.4.22.64) [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.
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. [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. [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. [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. [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]
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.
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. [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. [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. [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]
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.
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. [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. [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. [PMID: 9578463]
5. Martinon, F. and Tschopp, J. Inflammatory caspases: linking an intracellular innate immune system to autoinflammatory diseases. Cell 117 (2004) 561-574. [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]
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.
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. [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. [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. [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. [PMID: 9578463]
5. Martinon, F. and Tschopp, J. Inflammatory caspases: linking an intracellular innate immune system to autoinflammatory diseases. Cell 117 (2004) 561-574. [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]
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.
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. [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. [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. [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. [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. [PMID: 8710882]
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.
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. [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. [PMID: 12824163]
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.
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. [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. [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. [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. [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. [PMID: 15209560]
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-AspXaa
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.
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. [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. [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.
Accepted name: caspase-10
Reaction: Strict requirement for Asp at position P1 and has a preferred cleavage sequence of Leu-Gln-Thr-AspGly
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 3.4.22.44), 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.
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. [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. [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. [PMID: 15209560]
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.
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. [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. [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. [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]
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.
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. [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. [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. [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. [PMID: 16627476]
Accepted name: phosphonopyruvate hydrolase
Reaction: 3-phosphonopyruvate + H2O = pyruvate + phosphate
Other name(s): PPH
Comments: Highly specific for phosphonopyruvate as substrate [2]. The reaction is not inhibited by phosphate but is inhibited by the phosphonates phosphonoformic acid, hydroxymethylphosphonic acid and 3-phosphonopropanoic acid [2]. The enzyme is activated by the divalent cations Co2+, Mg2+ and Mn2+. This enzyme is a member of the phosphoenolpyruvate mutase/isocitrate lyase superfamily [3].
References:
1. Ternan, N.G., Hamilton, J.T. and Quinn, J.P. Initial in vitro characterisation of phosphonopyruvate hydrolase, a novel phosphate starvation-independent, carbon-phosphorus bond cleavage enzyme in Burkholderia cepacia Pal6. Arch. Microbiol. 173 (2000) 35-41. [PMID: 10648102]
2. Kulakova, A.N., Wisdom, G.B., Kulakov, L.A. and Quinn, J.P. The purification and characterization of phosphonopyruvate hydrolase, a novel carbon-phosphorus bond cleavage enzyme from Variovorax sp. Pal2. J. Biol. Chem. 278 (2003) 23426-23431. [PMID: 12697754]
3. Chen, C.C., Han, Y., Niu, W., Kulakova, A.N., Howard, A., Quinn, J.P., Dunaway-Mariano, D. and Herzberg, O. Structure and kinetics of phosphonopyruvate hydrolase from Variovorax sp. Pal2: new insight into the divergence of catalysis within the PEP mutase/isocitrate lyase superfamily. Biochemistry 45 (2006) 11491-11504. [PMID: 16981709]
Accepted name: chorismate lyase
Reaction: chorismate = 4-hydroxybenzoate + pyruvate
Other name(s): CL; CPL; UbiC
Systematic name: chorismate pyruvate-lyase (4-hydroxybenzoate-forming)
Comments: This enzyme catalyses the first step in the biosynthesis of ubiquinone in Escherichia coli and other Gram-negative bacteria [1]. The yeast Saccharomyces cerevisiae can synthesize ubiquinone from either chorismate or tyrosine [3].
References:
1. Nichols, B.P. and Green, J.M. Cloning and sequencing of Escherichia coli ubiC and purification of chorismate lyase. J. Bacteriol. 174 (1992) 5309-5316. [PMID: 1644758]
2. Siebert, M., Severin, K. and Heide, L. Formation of 4-hydroxybenzoate in Escherichia coli: characterization of the ubiC gene and its encoded enzyme chorismate pyruvate-lyase. Microbiology 140 (1994) 897-904. [PMID: 8012607]
3. Meganathan, R. Ubiquinone biosynthesis in microorganisms. FEMS Microbiol. Lett. 203 (2001) 131-139. [PMID: 11583838]
Accepted name: homoaconitate hydratase
Reaction: (1R,2S)-1-hydroxybutane-1,2,4-tricarboxylate = (Z)-but-1-ene-1,2,4-tricarboxylate + H2O
For diagram click here.
Glossary: cis-homoaconitate = (Z)-but-1-ene-1,2,4-tricarboxylate
homocitrate = (2R)-2-hydroxybutane-1,2,4-tricarboxylate
homoisocitrate = (1R,2S)-1-hydroxybutane-1,2,4-tricarboxylate
Other name(s): homoaconitase; cis-homoaconitase; HACN; Lys4; LysF; 2-hydroxybutane-1,2,4-tricarboxylate hydro-lyase (incorrect)
Systematic name: (1R,2S)-1-hydroxybutane-1,2,4-tricarboxylate hydro-lyase [(Z)-but-1-ene-1,2,4-tricarboxylate-forming]
Comments: Requires a [4Fe-4S] cluster for activity. The enzyme from the hyperthermophilic eubacterium Thermus thermophilus can catalyse the reaction shown above but cannot catalyse the previously described reaction, i.e. formation of homocitrate by hydration of cis-homoaconitate. The enzyme responsible for the conversion of cis-homoaconitate into homocitrate in T. thermophilus is unknown at present but the reaction can be catalysed in vitro using aconitate hydratase from pig (EC 4.2.1.3) [2].
Links to other databases: BRENDA, ERGO, EXPASY, KEGG, CAS registry number: 9030-68-6
References:
1. Strassman, M. and Ceci, L.N. Enzymatic formation of cis-homoaconitic acid, an intermediate in lysine biosynthesis in yeast. J. Biol. Chem. 241 (1966) 5401-5407. [PMID: 5954805]
2. Jia, Y., Tomita, T., Yamauchi, K., Nishiyama, M. and Palmer, D.R. Kinetics and product analysis of the reaction catalysed by recombinant homoaconitase from Thermus thermophilus. Biochem. J. 396 (2006) 479-485. [PMID: 16524361]
3. Zabriskie, T.M. and Jackson, M.D. Lysine biosynthesis and metabolism in fungi. Nat. Prod. Rep. 17 (2000) 85-97. [PMID: 10714900]
Accepted name: 2-methylcitrate dehydratase
Reaction: (2S,3S)-2-hydroxybutane-1,2,3-tricarboxylate = (Z)-but-2-ene-1,2,3-tricarboxylate + H2O
Glossary: (2S,3S)-2-methylcitrate = (2S,3S)-2-hydroxybutane-1,2,3-tricarboxylate
cis-2-methylaconitate = (Z)-but-2-ene-1,2,3-tricarboxylate
Other name(s): 2-methylcitrate hydro-lyase; PrpD; 2-hydroxybutane-1,2,3-tricarboxylate hydro-lyase
Systematic name: (2S,3S)-2-hydroxybutane-1,2,3-tricarboxylate hydro-lyase [(Z)-but-2-ene-1,2,3-tricarboxylate-forming]
Comments: Not identical with EC 4.2.1.4, citrate dehydratase. The enzyme is specific for (2S,3S)-methylcitrate, showing no activity with (2R,3S)-methylcitrate [2]. The enzyme can also use cis-aconitate as a substrate but more slowly [2]. Both this enzyme and EC 4.2.1.3, aconitate hydratase, are required to complete the isomerization of (2S,3S)-methylcitrate to (2R,3S)-2-methylisocitrate [2]
Links to other databases: BRENDA, ERGO, EXPASY, KEGG, PDB, CAS registry number: 80891-26-5
References:
1. Aoki, H. and Tabuchi, T. Purification and properties of 2-methylcitrate dehydratase from Yarrowia lipolytica. Agric. Biol. Chem. 45 (1981) 2831-2837.
2. Brock, M., Maerker, C., Schütz, A., Völker, U. and Buckel, W. Oxidation of propionate to pyruvate in Escherichia coli. Involvement of methylcitrate dehydratase and aconitase. Eur. J. Biochem. 269 (2002) 6184-6194. [PMID: 12473114]
Accepted name: cyanase
Reaction: cyanate + HCO3- + 2 H+ = NH3 + 2 CO2 (overall reaction)
(1a) cyanate + HCO3- + H+ = carbamate + CO2
(1b) carbamate + H+ = NH3 + CO2 (spontaneous)
For diagram click here.
Glossary: cyanate = NCO-
carbamate = H2N-CO-O-
Other name(s): cyanate lyase; cyanate hydrolase; cyanase; cyanate aminohydrolase; cyanate C-N-lyase; cyanate hydratase
Systematic name: carbamate hydro-lyase
Comments: This enzyme, which is found in bacteria and plants, is used to decompose cyanate, which can be used as the sole source of nitrogen [6,7]. Reaction (1) can be considered as the reverse of 'carbamate = cyanate + H2O', where this is assisted by reaction with bicarbonate and carbon dioxide (see mechanism above) [2], and hence is classified in sub-subclass 4.2.1. Bicarbonate functions as a recycling substrate [2].
Links to other databases: BRENDA, ERGO, EXPASY, KEGG, PDB, UM-BBD, CAS registry number: 37289-24-0
References:
1. Anderson, P.M. Purification and properties of the inducible enzyme cyanase. Biochemistry 19 (1980) 2882-2888. [PMID: 6994799]
2. Johnson, W.V. and Anderson, P.M. Bicarbonate is a recycling substrate for cyanase. J. Biol. Chem. 262 (1987) 9021-9025. [PMID: 3110153]
3. Taussig, A. The synthesis of the induced enzyme, "cyanase", in E. coli. Biochim. Biophys. Acta 44 (1960) 510-519. [PMID: 13775509]
4. Taussig, A. Some properties of the induced enzyme cyanase. Can. J. Biochem. 43 (1965) 1063-1069. [PMID: 5322950]
5. Anderson, P.M., Korte, J.J. and Holcomb, T.A. Reaction of the N-terminal methionine residues in cyanase with diethylpyrocarbonate. Biochemistry 33 (1994) 14121-14125. [PMID: 7947823]
6. Kozliak, E.I., Fuchs, J.A., Guilloton, M.B. and Anderson, P.M. Role of bicarbonate/CO2 in the inhibition of Escherichia coli growth by cyanate. J. Bacteriol. 177 (1995) 3213-3219. [PMID: 7768821]
7. Walsh, M.A., Otwinowski, Z., Perrakis, A., Anderson, P.M. and Joachimiak, A. Structure of cyanase reveals that a novel dimeric and decameric arrangement of subunits is required for formation of the enzyme active site. Structure 8 (2000) 505-514. [PMID: 10801492]
Accepted name: acetylene hydratase
Reaction: acetaldehyde = acetylene + H2O
Other name(s): AH
Systematic name: acetaldehyde hydro-lyase
Comments: This is a non-redox-active enzyme that contains two molybdopterin guanine dinucleotide (MGD) cofactors, a tungsten centre and a cubane type [4Fe-4S] cluster [2].The tungsten centre binds a water molecule that is activated by an adjacent aspartate residue, enabling it to attack acetylene bound in a distinct hydrophobic pocket [2]. Ethylene cannot act as a substrate [1].
References:
1. Rosner, B.M. and Schink, B. Purification and characterization of acetylene hydratase of Pelobacter acetylenicus, a tungsten iron-sulfur protein. J. Bacteriol. 177 (1995) 5767-5772. [PMID: 7592321]
2. Seiffert, G.B., Ullmann, G.M., Messerschmidt, A., Schink, B., Kroneck, P.M. and Einsle, O. Structure of the non-redox-active tungsten/[4Fe:4S] enzyme acetylene hydratase. Proc. Natl. Acad. Sci. USA 104 (2007) 3073-3077. [PMID: 17360611]
Accepted name: isoprene synthase
Reaction: dimethylallyl diphosphate = isoprene + diphosphate
For diagram of reaction click here
Glossary: isoprene = 2-methylbuta-1,3-diene
Other name(s): ISPC; ISPS
Systematic name: dimethylallyl-diphosphate diphosphate-lyase (isoprene-forming)
Comments: Requires Mg2+ or Mn2+ for activity. This enzyme is located in the chloroplast of isoprene-emitting plants, such as poplar and aspen, and may be activitated by light-dependent changes in chloroplast pH and Mg2+ concentration [2,8].
References:
1. Silver, G.M. and Fall, R. Enzymatic synthesis of isoprene from dimethylallyl diphosphate in aspen leaf extracts. Plant Physiol. 97 (1991) 1588-1591. [PMID: 16668590]
2. Silver, G.M. and Fall, R. Characterization of aspen isoprene synthase, an enzyme responsible for leaf isoprene emission to the atmosphere. J. Biol. Chem. 270 (1995) 13010-13016. [PMID: 7768893]
3. Wildermuth, M.C. and Fall, R. Light-dependent isoprene emission (characterization of a thylakoid-bound isoprene synthase in Salix discolor chloroplasts). Plant Physiol. 112 (1996) 171-182. [PMID: 12226383]
4. Schnitzler, J.P., Arenz, R., Steinbrecher, R. and Lehming, A. Characterization of an isoprene synthase from leaves of Quercus petraea. Bot. Acta 109 (1996) 216-221.
5. Miller, B., Oschinski, C. and Zimmer, W. First isolation of an isoprene synthase gene from poplar and successful expression of the gene in Escherichia coli. Planta 213 (2001) 483-487. [PMID: 11506373]
6. Sivy, T.L., Shirk, M.C. and Fall, R. Isoprene synthase activity parallels fluctuations of isoprene release during growth of Bacillus subtilis. Biochem. Biophys. Res. Commun. 294 (2002) 71-75. [PMID: 12054742]
7. Sasaki, K., Ohara, K. and Yazaki, K. Gene expression and characterization of isoprene synthase from Populus alba. FEBS Lett. 579 (2005) 2514-2518. [PMID: 15848197]
8. Schnitzler, J.-P., Zimmer, I., Bachl, A., Arend, M., Fromm, J. and Fischbach, R.J. Biochemical properties of isoprene synthase in poplar (Populus x canescens. Planta 222 (2005) 777-786. [PMID: 16052321]