Arachidonate epoxygenase / epoxide hydrolase (WP1250)

Mus musculus

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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

Egon Willighagen , Christine Chichester , Martina Summer-Kutmon , and Eric Weitz

Activity

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Organisms

Mus musculus

Communities

Annotations

Pathway Ontology

arachidonic acid metabolic pathway

Participants

Label Type Compact URI Comment
11,12-DiHETrE Metabolite hmdb:HMDB0002314
14(15)-EpETrE Metabolite hmdb:HMDB0004264
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
Ephx2 GeneProduct ncbigene:13850
Cox5a GeneProduct ncbigene:12858
Cox8a GeneProduct ncbigene:12868
Ephx2 GeneProduct ncbigene:13850 5(6)-EpETrE is a poor sEH substrate

References

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  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
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  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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