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


Decker, Martina; Adamska, Magdalena; Cronin, Annette; Di Giallonardo, Francesca; Burgener, Julia; Marowsky, Anne; Falck, John R; Morisseau, Christophe; Hammock, Bruce D; Gruzdev, Artiom; Zeldin, Darryl C; Arand, Michael (2012). EH3 (ABHD9): the first member of a new epoxide hydrolase family with high activity for fatty acid epoxides. Journal of Lipid Research, 53(10):2038-2045.

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.

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.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Pharmacology and Toxicology
07 Faculty of Science > Institute of Pharmacology and Toxicology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2012
Deposited On:19 Feb 2013 16:18
Last Modified:07 Dec 2017 19:33
Publisher:American Society for Biochemistry and Molecular Biology
ISSN:0022-2275
Additional Information:This research was originally published in Journal of Lipid Research. Decker, Martina; Adamska, Magdalena; Cronin, Annette; Di Giallonardo, Francesca; Burgener, Julia; Marowsky, Anne; Falck, John R; Morisseau, Christophe; Hammock, Bruce D; Gruzdev, Artiom; Zeldin, Darryl C; Arand, Michael (2012). EH3 (ABHD9): the first member of a new epoxide hydrolase family with high activity for fatty acid epoxides. Journal of Lipid Research, 53(10):2038-2045. © the American Society for Biochemistry and Molecular Biology.
Publisher DOI:https://doi.org/10.1194/jlr.M024448
PubMed ID:22798687

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