Arachidonate epoxygenase / epoxide hydrolase (WP678)

Homo sapiens

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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.

Authors

Martijn Van Iersel , Chris Evelo , John W. Newman , Thomas Kelder , Alex Pico , Kristina Hanspers , Christine Chichester , Denise Slenter , Eric Weitz , and Egon Willighagen

Activity

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Organisms

Homo sapiens

Communities

Annotations

Pathway Ontology

metabolic pathway of secondary metabolites arachidonic acid metabolic pathway

Participants
Query Drugst.One

Label Type Compact URI Comment
11,12-DiHETrE Metabolite hmdb:HMDB0002314
14(15)-EpETrE Metabolite hmdb:HMDB0004264
5(6)-Epoxy-PGE1 Metabolite pubchem.compound:53481368
5,6-DiHETrE Metabolite hmdb:HMDB0002343
8(9)-EpETrE Metabolite hmdb:HMDB0002232
5(6)-EpETrE Metabolite hmdb:HMDB0002190
11(12)-EpETrE Metabolite hmdb:HMDB0010409
8,9-DiHETrE Metabolite hmdb:HMDB0002311
14,15-DiHETrE Metabolite hmdb:HMDB0002265
Arachidonic acid Metabolite hmdb:HMDB0001043
CYP2C9 GeneProduct ncbigene:1559
EPHX2 GeneProduct ncbigene:2053
COX GeneProduct ncbigene:9377
EPHX2 GeneProduct ncbigene:2053
EPHX2 GeneProduct ncbigene:2053
CYP2C8 GeneProduct ncbigene:1558
GST3 GeneProduct ncbigene:2950
COX GeneProduct ncbigene:1351
CYP2J2 GeneProduct ensembl:ENSG00000134716
EPHX2 GeneProduct ncbigene:2053 5(6)-EpETrE is a poor sEH substrate
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References

  1. Novel renal arachidonate metabolites. Carroll MA, Schwartzman M, Sacerdoti D, McGiff JC. Am J Med Sci. 1988 Apr;295(4):268–74. PubMed Europe PMC Scholia
  2. A novel pool of rat liver inositol and ethanolamine phospholipids contains epoxyeicosatrienoic acids (EETs). Capdevila JH, Kishore V, Dishman E, Blair IA, Falck JR. Biochem Biophys Res Commun. 1987 Jul 31;146(2):638–44. PubMed Europe PMC Scholia
  3. On the metabolism of epoxyeicosatrienoic acids by ram seminal vesicles: isolation of 5(6)epoxy-prostaglandin F1 alpha. Oliw EH, Benthin G. Biochem Biophys Res Commun. 1985 Feb 15;126(3):1090–6. PubMed Europe PMC Scholia
  4. Novel glutathione conjugates formed from epoxyeicosatrienoic acids (EETs). Spearman ME, Prough RA, Estabrook RW, Falck JR, Manna S, Leibman KC, et al. Arch Biochem Biophys. 1985 Oct;242(1):225–30. PubMed Europe PMC Scholia
  5. Biosynthesis of 5,6-dihydroxyprostaglandin E1 and F1 alpha from 5,6-dihydroxyeicosatrienoic acid by ram seminal vesicles. Oliw EH. Biochim Biophys Acta. 1984 Sep 12;795(2):384–91. PubMed Europe PMC Scholia
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  12. Epoxyeicosatrienoic and dihydroxyeicosatrienoic acids dilate human coronary arterioles via BK(Ca) channels: implications for soluble epoxide hydrolase inhibition. Larsen BT, Miura H, Hatoum OA, Campbell WB, Hammock BD, Zeldin DC, et al. Am J Physiol Heart Circ Physiol. 2006 Feb;290(2):H491-9. PubMed Europe PMC Scholia
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  14. Soluble epoxide hydrolase inhibition reveals novel biological functions of epoxyeicosatrienoic acids (EETs). Inceoglu B, Schmelzer KR, Morisseau C, Jinks SL, Hammock BD. Prostaglandins Other Lipid Mediat. 2007 Jan;82(1–4):42–9. PubMed Europe PMC Scholia
  15. Epoxyeicosatrienoic acids affect electrolyte transport in renal tubular epithelial cells: dependence on cyclooxygenase and cell polarity. Nüsing RM, Schweer H, Fleming I, Zeldin DC, Wegmann M. Am J Physiol Renal Physiol. 2007 Jul;293(1):F288-98. PubMed Europe PMC Scholia
  16. Hydrogen peroxide inhibits cytochrome p450 epoxygenases: interaction between two endothelium-derived hyperpolarizing factors. Larsen BT, Gutterman DD, Sato A, Toyama K, Campbell WB, Zeldin DC, et al. Circ Res. 2008 Jan 4;102(1):59–67. PubMed Europe PMC Scholia
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  18. Gerry Brooks and epoxide hydrolases: four decades to a pharmaceutical. Morisseau C, Hammock BD. Pest Manag Sci. 2008 Jun;64(6):594–609. PubMed Europe PMC Scholia