Arachidonate epoxygenase / epoxide hydrolase (Bos taurus)

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1-7, 9, 10, 13...ProductProductCYP2C8Phosphotidyl-EpETrEsCOX11,12-DiHETrEGSTP1CYP2C95(6)-Epoxy-PGE1EPHX2COX5A11(12)-EpETrEArachidonic acid8(9)-EpETrEGlutathionyl-HETrEs5,6-DiH-PGF1a5(6)-EpETrECYP2J28,9-DiHETrEEPHX214,15-DiHETrE5,6-DiHETrEEPHX2EPHX2Catalyst14(15)-EpETrE8313127, 132, 1022, 1013, 163, 11, 12, 16


Description

The cytochrome P450-dependent formation of polyunsaturated fatty acid epoxides is an important biochemical pathway creating mediators of inflammation and blood pressure regulation. Once formed these compounds can be incorperated into phospholipid membrance, and released by the action of phospholipase A2. The epoxides of arachidonic acid, i.e. the epoxyeicosatrieneoic acid or EETs, are putative endothelial derived hyperpolarization factors which increase the open state probability of Ca++ sensitive K+ channels, leading to vasodilation in arteriolar beds. The 11(12)-EET in particular appears to have potent functions in vasodilation, and are inhibitors of NFKb dependent inflammatory signalling, and PAI-1 activity. The 5(6)-EET appears unique, in that its metabolic transformation through cyclooxygenase activities produces potent vasoconstrictors. With the exception of the 5(6)-EET, these epoxy fatty acids are good substrates for the soluble epoxide hydrolase. Hydrolytic tranformation to vicinal diols eliminates vasoactive actions, however these vicinal diols have been reported to have other biological activites, including PPAR-alpha activation. Recent development of inhibitors of the soluble epoxide hydrolase are proving to have potent anti-inflammatory, anti-hypertensive, and anti-nociceptive properties. Reports of enzyme catalyzed glutathione-conjugates of the epoxy fatty acids have been reported, but the activity and relavance of these potential metabolic products are unknown to date.

Comments

 
Fatty Acid Epoxygenase
 
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HomologyConvert 
This pathway was inferred from Homo sapiens pathway WP678(r30254) with a 54% conversion rate.

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Bibliography

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  1. Sacerdoti D, Gatta A, McGiff JC; ''Role of cytochrome P450-dependent arachidonic acid metabolites in liver physiology and pathophysiology.''; Prostaglandins Other Lipid Mediat, 2003 PubMed Europe PMC Scholia
  2. Capdevila JH, Kishore V, Dishman E, Blair IA, Falck JR; ''A novel pool of rat liver inositol and ethanolamine phospholipids contains epoxyeicosatrienoic acids (EETs).''; Biochem Biophys Res Commun, 1987 PubMed Europe PMC Scholia
  3. Oliw EH, Benthin G; ''On the metabolism of epoxyeicosatrienoic acids by ram seminal vesicles: isolation of 5(6)epoxy-prostaglandin F1 alpha.''; Biochem Biophys Res Commun, 1985 PubMed Europe PMC Scholia
  4. Spector AA, Fang X, Snyder GD, Weintraub NL; ''Epoxyeicosatrienoic acids (EETs): metabolism and biochemical function.''; Prog Lipid Res, 2004 PubMed Europe PMC Scholia
  5. Carroll MA, Schwartzman M, Sacerdoti D, McGiff JC; ''Novel renal arachidonate metabolites.''; Am J Med Sci, 1988 PubMed Europe PMC Scholia
  6. Morisseau C, Hammock BD; ''Gerry Brooks and epoxide hydrolases: four decades to a pharmaceutical.''; Pest Manag Sci, 2008 PubMed Europe PMC Scholia
  7. Inceoglu B, Schmelzer KR, Morisseau C, Jinks SL, Hammock BD; ''Soluble epoxide hydrolase inhibition reveals novel biological functions of epoxyeicosatrienoic acids (EETs).''; Prostaglandins Other Lipid Mediat, 2007 PubMed Europe PMC Scholia
  8. Vriens J, Owsianik G, Fisslthaler B, Suzuki M, Janssens A, Voets T, Morisseau C, Hammock BD, Fleming I, Busse R, Nilius B; ''Modulation of the Ca2 permeable cation channel TRPV4 by cytochrome P450 epoxygenases in vascular endothelium.''; Circ Res, 2005 PubMed Europe PMC Scholia
  9. Mannervik B, Board PG, Hayes JD, Listowsky I, Pearson WR; ''Nomenclature for mammalian soluble glutathione transferases.''; Methods Enzymol, 2005 PubMed Europe PMC Scholia
  10. Newman JW, Morisseau C, Hammock BD; ''Epoxide hydrolases: their roles and interactions with lipid metabolism.''; Prog Lipid Res, 2005 PubMed Europe PMC Scholia
  11. Zhang L, Ding H, Yan J, Hui R, Wang W, Kissling GE, Zeldin DC, Wang DW; ''Genetic variation in cytochrome P450 2J2 and soluble epoxide hydrolase and risk of ischemic stroke in a Chinese population.''; Pharmacogenet Genomics, 2008 PubMed Europe PMC Scholia
  12. Sarkis A, Roman RJ; ''Role of cytochrome P450 metabolites of arachidonic acid in hypertension.''; Curr Drug Metab, 2004 PubMed Europe PMC Scholia
  13. Spearman ME, Prough RA, Estabrook RW, Falck JR, Manna S, Leibman KC, Murphy RC, Capdevila J; ''Novel glutathione conjugates formed from epoxyeicosatrienoic acids (EETs).''; Arch Biochem Biophys, 1985 PubMed Europe PMC Scholia
  14. Oliw EH; ''Biosynthesis of 5,6-dihydroxyprostaglandin E1 and F1 alpha from 5,6-dihydroxyeicosatrienoic acid by ram seminal vesicles.''; Biochim Biophys Acta, 1984 PubMed Europe PMC Scholia
  15. Larsen BT, Gutterman DD, Sato A, Toyama K, Campbell WB, Zeldin DC, Manthati VL, Falck JR, Miura H; ''Hydrogen peroxide inhibits cytochrome p450 epoxygenases: interaction between two endothelium-derived hyperpolarizing factors.''; Circ Res, 2008 PubMed Europe PMC Scholia
  16. Harder DR, Roman RJ, Gebremedhin D; ''Molecular mechanisms controlling nutritive blood flow: role of cytochrome P450 enzymes.''; Acta Physiol Scand, 2000 PubMed Europe PMC Scholia
  17. N�sing RM, Schweer H, Fleming I, Zeldin DC, Wegmann M; ''Epoxyeicosatrienoic acids affect electrolyte transport in renal tubular epithelial cells: dependence on cyclooxygenase and cell polarity.''; Am J Physiol Renal Physiol, 2007 PubMed Europe PMC Scholia
  18. Larsen BT, Miura H, Hatoum OA, Campbell WB, Hammock BD, Zeldin DC, Falck JR, Gutterman DD; ''Epoxyeicosatrienoic and dihydroxyeicosatrienoic acids dilate human coronary arterioles via BK(Ca) channels: implications for soluble epoxide hydrolase inhibition.''; Am J Physiol Heart Circ Physiol, 2006 PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
134190view18:19, 16 July 2024EgonwRemoved template comments
117475view10:58, 21 May 2021EweitzModified title
105965view11:49, 16 August 2019MaintBotHMDB identifier normalization
80835view15:27, 30 June 2015Mkutmonhomology conversion
74149view11:34, 1 April 2014EgonwReplaced an InChI with a more traditional identifier.
71404view19:00, 17 October 2013MaintBotAutomated update of data sources
63337view21:13, 9 May 2013MaintBotUpdated to 2013 gpml schema
53462view19:03, 7 November 2012EgonwReplaced HMDB with InChI.
53461view19:00, 7 November 2012EgonwRDF Tidy
40517view19:29, 1 March 2011MaintBotRemoved redundant pathway information and comments
33760view00:02, 9 December 2009MaintBotAutomatic update of empty xrefs
31647view11:36, 14 August 2009MaintBotFixed group labels
30569view22:05, 29 July 2009MaintBotNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
11(12)-EpETrEMetaboliteHMDB10409 (HMDB)
11,12-DiHETrEMetaboliteHMDB02314 (HMDB)
14(15)-EpETrEMetaboliteHMDB04264 (HMDB)
14,15-DiHETrEMetaboliteHMDB02265 (HMDB)
5(6)-EpETrEMetaboliteHMDB02190 (HMDB)
5(6)-Epoxy-PGE1MetaboliteInChI=1S/C20H32O6/c1-2-3-4-6-13(21)9-10-14-15(17(23)12-16(14)22)11-19-18(26-19)7-5-8-20(24)25/h9-10,13-16,18-19,21-22H,2-8,11-12H2,1H3,(H,24,25)/b10-9+/t13-,14-,15-,16-,18?,19?/m0/s1 (InChI)
5,6-DiH-PGF1aMetabolite
5,6-DiHETrEMetaboliteHMDB02343 (HMDB)
8(9)-EpETrEMetaboliteHMDB02232 (HMDB)
8,9-DiHETrEMetaboliteHMDB02311 (HMDB)
Arachidonic acidMetaboliteHMDB01043 (HMDB)
COXGeneProduct
COX5AGeneProduct444878 (Entrez Gene)
CYP2C8GeneProduct
CYP2C9GeneProduct
CYP2J2GeneProduct521656 (Entrez Gene)
CatalystGeneProduct
EPHX2GeneProduct511716 (Entrez Gene)
GSTP1GeneProduct281806 (Entrez Gene)
Glutathionyl-HETrEsMetabolite
Phosphotidyl-EpETrEsMetabolite

Annotated Interactions

No annotated interactions
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