EH3 (ABHD9): The first member of a new epoxide hydrolase family with high activity for fatty acid epoxides

Martina Decker, Magdalena Adamska, Annette Cronin, Francesca Di Giallonardo, Julia Burgener, Anne Marowsky, J R Falck, Christophe Morisseau, Bruce D. Hammock, Artiom Gruzdev, Darryl C. Zeldin, Michael Arand

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

Epoxide hydrolases are a small superfamily of enzymes important for the detoxification of chemically reactive xenobiotic epoxides and for the processing of endogenous epoxides that act as signaling molecules. Here, we report the identification of two human epoxide hydrolases: EH3 and EH4. They share 45% sequence identity, thus representing a new family of mammalian epoxide hydrolases. Quantitative RT-PCR from mouse tissue indicates strongest EH3 expression in lung, skin, and upper gastrointestinal tract. The recombinant enzyme shows a high turnover number with 8,9-, 11,12-, and 14,15- epoxyeicosatrienoic acid (EET), as well as 9,10-epoxyoctadec-11-enoic acid (leukotoxin). It is inhibited by a subclass of N,N′-disubstituted urea derivatives, including 12-(3-adamantan-1-yl-ureido)-dodecanoic acid, 1-cyclohexyl-3-dodecylurea, and 1-(1-acetylpiperidin-4-yl)-3-(4- (trifluoromethoxy)phenyl)urea, compounds so far believed to be selective inhibitors of mammalian soluble epoxide hydrolase (sEH). Its sensitivity to this subset of sEH inhibitors may have implications on the pharmacologic profile of these compounds. This is particularly relevant because sEH is a potential drug target, and clinical trials are under way exploring the value of sEH inhibitors in the treatment of hypertension and diabetes type II.

Original languageEnglish (US)
Pages (from-to)2038-2045
Number of pages8
JournalJournal of lipid research
Volume53
Issue number10
DOIs
StatePublished - Oct 2012

Keywords

  • Blood pressure
  • Diabetes type II
  • Epoxyeicosatrienoic acid
  • Pain

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

Fingerprint Dive into the research topics of 'EH3 (ABHD9): The first member of a new epoxide hydrolase family with high activity for fatty acid epoxides'. Together they form a unique fingerprint.

Cite this