EC |
1.13.11.31 |
Accepted name: |
arachidonate 12-lipoxygenase |
Reaction: |
arachidonate + O2 = (5Z,8Z,10E,14Z)-(12S)-12-hydroperoxyicosa-5,8,10,14-tetraenoate |
Other name(s): |
Δ12-lipoxygenase; 12-lipoxygenase; 12Δ-lipoxygenase; C-12 lipoxygenase; 12S-lipoxygenase; leukotriene A4 synthase; LTA4 synthase |
Systematic name: |
arachidonate:oxygen 12-oxidoreductase |
Comments: |
The product is rapidly reduced to the corresponding 12S-hydroxy compound. |
Links to other databases: |
BRENDA, EXPASY, KEGG, MetaCyc, PDB, CAS registry number: 82391-43-3 |
References: |
1. |
Hamberg, M. and Samuelsson, B. Prostaglandin endoperoxides. Novel transformations of arachidonic acid in human platelets. Proc. Natl. Acad. Sci. USA 71 (1974) 3400–3404. [DOI] [PMID: 4215079] |
2. |
Nugteren, D.H. Arachidonate lipoxygenase in blood platelets. Biochim. Biophys. Acta 380 (1975) 299–307. [DOI] [PMID: 804329] |
3. |
Wallach, D.P. and Brown, V.R. A novel preparation of human platelet lipoxygenase. Characteristics and inhibition by a variety of phenyl hydrazones and comparisons with other lipoxygenases. Biochim. Biophys. Acta 663 (1981) 361–372. [DOI] [PMID: 6783111] |
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[EC 1.13.11.31 created 1983] |
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EC |
1.13.11.34 |
Accepted name: |
arachidonate 5-lipoxygenase |
Reaction: |
arachidonate + O2 = leukotriene A4 + H2O (overall reaction) (1a) arachidonate + O2 = (6E,8Z,11Z,14Z)-(5S)-5-hydroperoxyicosa-6,8,11,14-tetraenoate (1b) (6E,8Z,11Z,14Z)-(5S)-5-hydroperoxyicosa-6,8,11,14-tetraenoate = leukotriene A4 + H2O |
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For diagram of leukotriene biosynthesis, click here |
Glossary: |
leukotriene A4 = (7E,9E,11Z,14Z)-(5S,6S)-5,6-epoxyicosa-7,9,11,14-tetraenoate |
Other name(s): |
leukotriene-A4 synthase; Δ5-lipoxygenase; 5Δ-lipoxygenase; arachidonic 5-lipoxygenase; arachidonic acid 5-lipoxygenase; C-5-lipoxygenase; LTA synthase; leukotriene A4 synthase |
Systematic name: |
arachidonate:oxygen 5-oxidoreductase |
Links to other databases: |
BRENDA, EXPASY, KEGG, MetaCyc, PDB, CAS registry number: 80619-02-9 |
References: |
1. |
Matsumoto, T., Funk, C.D., Radmark, O., Hoog, J.-O., Jornvall, H. and Samuelsson, B. Molecular cloning and amino acid sequence of human 5-lipoxygenase. Proc. Natl. Acad. Sci. USA 85 (1988) 26–30. [DOI] [PMID: 2829172] |
2. |
Ohishi, N., Izumi, T., Minami, M., Kitamura, S., Seyama, Y., Ohkawa, S., Terao, S., Yotsumoto, H., Takaku, F. and Shimizu, T. Leukotriene A4 hydrolase in the human lung. Inactivation of the enzyme with leukotriene A4 isomers. J. Biol. Chem. 262 (1987) 10200–10205. [PMID: 3038871] |
3. |
Shimizu, T., Izumi, T., Seyama, Y., Tadokoro, K., Rädmark, O. and Samuelsson, B. Characterization of leukotriene A4 synthase from murine mast cells: evidence for its identity to arachidonate 5-lipoxygenase. Proc. Natl. Acad. Sci. USA 83 (1986) 4175–4179. [DOI] [PMID: 3012557] |
4. |
Shimizu, T., Rädmark, O. and Samuelssohn, B. Enzyme with dual lipoxygenase activities catalyzes leukotriene A4 synthesis from arachidonic acid. Proc. Natl. Acad. Sci. USA 81 (1984) 689–693. [DOI] [PMID: 6322165] |
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[EC 1.13.11.34 created 1984, modified 1990] |
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EC |
3.3.2.6 |
Accepted name: |
leukotriene-A4 hydrolase |
Reaction: |
leukotriene A4 + H2O = leukotriene B4 |
Glossary: |
leukotriene A4 = (7E,9E,11Z,14Z)-(5S,6S)-5,6-epoxyicosa-7,9,11,14-tetraenoate
leukotriene B4 = (6Z,8E,10E,14Z)-(5S,12R)-5,12-dihydroxyicosa-6,8,10,14-tetraenoate |
Other name(s): |
LTA4 hydrolase; LTA4H; leukotriene A4 hydrolase |
Systematic name: |
(7E,9E,11Z,14Z)-(5S,6S)-5,6-epoxyicosa-7,9,11,14-tetraenoate hydrolase |
Comments: |
This is a bifunctional zinc metalloprotease that displays both epoxide hydrolase and aminopeptidase activities [4,6]. It preferentially cleaves tripeptides at an arginyl bond, with dipeptides and tetrapeptides being poorer substrates [6] (see EC 3.4.11.6, aminopeptidase B). It also converts leukotriene A4 into leukotriene B4, unlike EC 3.3.2.10, soluble epoxide hydrolase, which converts leukotriene A4 into 5,6-dihydroxy-7,9,11,14-icosatetraenoic acid [3,4]. In vertebrates, five epoxide-hydrolase enzymes have been identified to date: EC 3.3.2.6 (leukotriene A4 hydrolase), EC 3.3.2.7 (hepoxilin-epoxide hydrolase), EC 3.3.2.9 (microsomal epoxide hydrolase), EC 3.3.2.10 (soluble epoxide hydrolase) and EC 3.3.2.11 (cholesterol-5,6-oxide hydrolase) [5]. |
Links to other databases: |
BRENDA, EXPASY, KEGG, MetaCyc, PDB, CAS registry number: 90119-07-6 |
References: |
1. |
Evans, J.F., Dupuis, P. and Ford-Hutchinson, A.W. Purification and characterisation of leukotriene A4 hydrolase from rat neutrophils. Biochim. Biophys. Acta 840 (1985) 43–50. [DOI] [PMID: 3995081] |
2. |
Minami, M., Ohno, S., Kawasaki, H., Rådmark, O., Samuelsson, B., Jörnvall, H., Shimizu, T., Seyama, Y. and Suzuki, K. Molecular cloning of a cDNA coding for human leukotriene A4 hydrolase - complete primary structure of an enzyme involved in eicosanoid synthesis. J. Biol. Chem. 262 (1987) 13873–13876. [PMID: 3654641] |
3. |
Haeggström, J., Meijer, J. and Rådmark, O. Leukotriene A4. Enzymatic conversion into 5,6-dihydroxy-7,9,11,14-eicosatetraenoic acid by mouse liver cytosolic epoxide hydrolase. J. Biol. Chem. 261 (1986) 6332–6337. [PMID: 3009453] |
4. |
Newman, J.W., Morisseau, C. and Hammock, B.D. Epoxide hydrolases: their roles and interactions with lipid metabolism. Prog. Lipid Res. 44 (2005) 1–51. [DOI] [PMID: 15748653] |
5. |
Fretland, A.J. and Omiecinski, C.J. Epoxide hydrolases: biochemistry and molecular biology. Chem. Biol. Interact. 129 (2000) 41–59. [DOI] [PMID: 11154734] |
6. |
Orning, L., Gierse, J.K. and Fitzpatrick, F.A. The bifunctional enzyme leukotriene-A4 hydrolase is an arginine aminopeptidase of high efficiency and specificity. J. Biol. Chem. 269 (1994) 11269. [PMID: 8157657] |
7. |
Ohishi, N., Izumi, T., Minami, M., Kitamura, S., Seyama, Y., Ohkawa, S., Terao, S., Yotsumoto, H., Takaku, F. and Shimizu, T. Leukotriene A4 hydrolase in the human lung. Inactivation of the enzyme with leukotriene A4 isomers. J. Biol. Chem. 262 (1987) 10200–10205. [PMID: 3038871] |
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[EC 3.3.2.6 created 1989, modified 2006] |
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EC |
3.3.2.7 |
Accepted name: |
hepoxilin-epoxide hydrolase |
Reaction: |
hepoxilin A3 + H2O = trioxilin A3 |
Glossary: |
hepoxilin A3 = (5Z,9E,14Z)-(8ξ,11R,12S)-11,12-epoxy-8-hydroxyicosa-5,9,14-trienoate
trioxilin A3 = (5Z,9E,14Z)-(8ξ,11ξ,12S)-8,11,12-trihydroxyicosa-5,9,14-trienoate |
Other name(s): |
hepoxilin epoxide hydrolase; hepoxylin hydrolase; hepoxilin A3 hydrolase |
Systematic name: |
(5Z,9E,14Z)-(8ξ,11R,12S)-11,12-epoxy-8-hydroxyicosa-5,9,14-trienoate hydrolase |
Comments: |
Converts hepoxilin A3 into trioxilin A3. Highly specific for the substrate, having only slight activity with other epoxides such as leukotriene A4 and styrene oxide [2]. Hepoxilin A3 is an hydroxy-epoxide derivative of arachidonic acid that is formed via the 12-lipoxygenase pathway [2]. It is probable that this enzyme plays a modulatory role in inflammation, vascular physiology, systemic glucose metabolism and neurological function [4]. In vertebrates, five epoxide-hydrolase enzymes have been identified to date: EC 3.3.2.6 (leukotriene-A4 hydrolase), EC 3.3.2.7 (hepoxilin-epoxide hydrolase), EC 3.3.2.9 (microsomal epoxide hydrolase), EC 3.3.2.10 (soluble epoxide hydrolase) and EC 3.3.2.11 (cholesterol 5,6-oxide hydrolase) [3]. |
Links to other databases: |
BRENDA, EXPASY, KEGG, MetaCyc, CAS registry number: 122096-98-4 |
References: |
1. |
Pace-Asciak, C.R. Formation and metabolism of hepoxilin A3 by the rat brain. Biochem. Biophys. Res. Commun. 151 (1988) 493–498. [DOI] [PMID: 3348791] |
2. |
Pace-Asciak, C.R. and Lee, W.-S. Purification of hepoxilin epoxide hydrolase from rat liver. J. Biol. Chem. 264 (1989) 9310–9313. [PMID: 2722835] |
3. |
Fretland, A.J. and Omiecinski, C.J. Epoxide hydrolases: biochemistry and molecular biology. Chem. Biol. Interact. 129 (2000) 41–59. [DOI] [PMID: 11154734] |
4. |
Newman, J.W., Morisseau, C. and Hammock, B.D. Epoxide hydrolases: their roles and interactions with lipid metabolism. Prog. Lipid Res. 44 (2005) 1–51. [DOI] [PMID: 15748653] |
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[EC 3.3.2.7 created 1992, modified 2006] |
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EC |
3.3.2.10 |
Accepted name: |
soluble epoxide hydrolase |
Reaction: |
an epoxide + H2O = a glycol |
Other name(s): |
epoxide hydrase (ambiguous); epoxide hydratase (ambiguous); arene-oxide hydratase (ambiguous); aryl epoxide hydrase (ambiguous); trans-stilbene oxide hydrolase; sEH; cytosolic epoxide hydrolase |
Systematic name: |
epoxide hydrolase |
Comments: |
Catalyses the hydrolysis of trans-substituted epoxides, such as trans-stilbene oxide, as well as various aliphatic epoxides derived from fatty-acid metabolism [7]. It is involved in the metabolism of arachidonic epoxides (epoxyicosatrienoic acids; EETs) and linoleic acid epoxides. The EETs, which are endogenous chemical mediators, act at the vascular, renal and cardiac levels to regulate blood pressure [4,5]. The enzyme from mammals is a bifunctional enzyme: the C-terminal domain exhibits epoxide-hydrolase activity and the N-terminal domain has the activity of EC 3.1.3.76, lipid-phosphate phosphatase [1,2]. Like EC 3.3.2.9, microsomal epoxide hydrolase, it is probable that the reaction involves the formation of an hydroxyalkyl—enzyme intermediate [4,6]. The enzyme can also use leukotriene A4, the substrate of EC 3.3.2.6, leukotriene-A4 hydrolase, but it forms 5,6-dihydroxy-7,9,11,14-icosatetraenoic acid rather than leukotriene B4 as the product [9,10]. In vertebrates, five epoxide-hydrolase enzymes have been identified to date: EC 3.3.2.6 (leukotriene-A4 hydrolase), EC 3.3.2.7 (hepoxilin-epoxide hydrolase), EC 3.3.2.9 (microsomal epoxide hydrolase), EC 3.3.2.10 (soluble epoxide hydrolase) and EC 3.3.2.11 (cholesterol 5,6-oxide hydrolase) [7]. |
Links to other databases: |
BRENDA, EAWAG-BBD, EXPASY, KEGG, MetaCyc, PDB, CAS registry number: 9048-63-9 |
References: |
1. |
Newman, J.W., Morisseau, C., Harris, T.R. and Hammock, B.D. The soluble epoxide hydrolase encoded by EPXH2 is a bifunctional enzyme
with novel lipid phosphate phosphatase activity. Proc. Natl. Acad. Sci. USA 100 (2003) 1558–1563. [DOI] [PMID: 12574510] |
2. |
Cronin, A., Mowbray, S., Dürk, H., Homburg, S., Fleming, I., Fisslthaler, B., Oesch, F. and Arand, M. The N-terminal domain of mammalian soluble epoxide hydrolase is a phosphatase. Proc. Natl. Acad. Sci. USA 100 (2003) 1552–1557. [DOI] [PMID: 12574508] |
3. |
Oesch, F. Mammalian epoxide hydrases: inducible enzymes catalysing the inactivation of carcinogenic and cytotoxic metabolites derived from aromatic and olefinic compounds. Xenobiotica 3 (1973) 305–340. [DOI] [PMID: 4584115] |
4. |
Morisseau, C. and Hammock, B.D. Epoxide hydrolases: mechanisms, inhibitor designs, and biological roles. Annu. Rev. Pharmacol. Toxicol. 45 (2005) 311–333. [DOI] [PMID: 15822179] |
5. |
Yu, Z., Xu, F., Huse, L.M., Morisseau, C., Draper, A.J., Newman, J.W., Parker, C., Graham, L., Engler, M.M., Hammock, B.D., Zeldin, D.C. and Kroetz, D.L. Soluble epoxide hydrolase regulates hydrolysis of vasoactive
epoxyeicosatrienoic acids. Circ. Res. 87 (2000) 992–998. [PMID: 11090543] |
6. |
Lacourciere, G.M. and Armstrong, R.N. The catalytic mechanism of microsomal epoxide hydrolase involves an ester intermediate. J. Am. Chem. Soc. 115 (1993) 10466. |
7. |
Fretland, A.J. and Omiecinski, C.J. Epoxide hydrolases: biochemistry and molecular biology. Chem. Biol. Interact. 129 (2000) 41–59. [DOI] [PMID: 11154734] |
8. |
Zeldin, D.C., Wei, S., Falck, J.R., Hammock, B.D., Snapper, J.R. and Capdevila, J.H. Metabolism of epoxyeicosatrienoic acids by cytosolic epoxide hydrolase:
substrate structural determinants of asymmetric catalysis. Arch. Biochem. Biophys. 316 (1995) 443–451. [DOI] [PMID: 7840649] |
9. |
Haeggström, J., Meijer, J. and Rådmark, O. Leukotriene A4. Enzymatic conversion into 5,6-dihydroxy-7,9,11,14-eicosatetraenoic acid by mouse liver cytosolic epoxide hydrolase. J. Biol. Chem. 261 (1986) 6332–6337. [PMID: 3009453] |
10. |
Newman, J.W., Morisseau, C. and Hammock, B.D. Epoxide hydrolases: their roles and interactions with lipid metabolism. Prog. Lipid Res. 44 (2005) 1–51. [DOI] [PMID: 15748653] |
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[EC 3.3.2.10 created 2006 (EC 3.3.2.3 created 1978, part incorporated 2006)] |
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EC |
4.4.1.20 |
Accepted name: |
leukotriene-C4 synthase |
Reaction: |
leukotriene C4 = leukotriene A4 + glutathione |
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For diagram of leukotriene biosynthesis, click here |
Glossary: |
leukotriene C4 = (7E,9E,11Z,14Z)-(5S,6R)-6-(glutathion-S-yl)-5-hydroxyicosa-7,9,11,14-tetraenoate
leukotriene A4 = (7E,9E,11Z,14Z)-(5S,6S)-5,6-epoxyicosa-7,9,11,14-tetraenoate |
Other name(s): |
leukotriene C4 synthetase; LTC4 synthase; LTC4 synthetase; leukotriene A4:glutathione S-leukotrienyltransferase; (7E,9E,11Z,14Z)-(5S,6R)-5,6-epoxyicosa-7,9,11,14-tetraenoate:glutathione leukotriene-transferase (epoxide-ring-opening); (7E,9E,11Z,14Z)-(5S,6R)-6-(glutathion-S-yl)-5-hydroxyicosa-7,9,11,14-tetraenoate glutathione-lyase (epoxide-forming) |
Systematic name: |
leukotriene-C4 glutathione-lyase (leukotriene-A4-forming) |
Comments: |
The reaction proceeds in the direction of addition. Not identical with EC 2.5.1.18, glutathione transferase. |
Links to other databases: |
BRENDA, EXPASY, KEGG, MetaCyc, PDB, CAS registry number: 90698-32-1 |
References: |
1. |
Bach, M.K., Brashler, J.R. and Morton, D.R., Jr. Solubilization and characterization of the leukotriene C4 synthetase of rat basophil leukemia cells: a novel, particulate glutathione S-transferase. Arch. Biochem. Biophys. 230 (1984) 455–465. [DOI] [PMID: 6324687] |
2. |
Shimizu, T. Enzymes functional in the syntheses of leukotrienes and related compounds. Int. J. Biochem. 20 (1988) 661–666. [PMID: 2846379] |
3. |
Lam, B.K. and Austen, K.F. Leukotriene C4 synthase: a pivotal enzyme in cellular biosynthesis of the cysteinyl leukotrienes. Prostaglandins Other Lipid Mediat. 68-69 (2002) 511–520. [DOI] [PMID: 12432940] |
4. |
Christmas, P., Weber, B.M., McKee, M., Brown, D. and Soberman, R.J. Membrane localization and topology of leukotriene C4 synthase. J. Biol. Chem. 277 (2002) 28902–28908. [DOI] [PMID: 12023288] |
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[EC 4.4.1.20 created 1989 as EC 2.5.1.37, transferred 2004 to EC 4.4.1.20] |
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