EH3 (ABHD9): the first member of a new epoxide hydrolase family with high activity for fatty acid epoxides
EH3 (ABHD9): the first member of a new epoxide hydrolase family with high activity for fatty acid epoxides
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DOI：
10.1194/jlr.m024448
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发表时间：
2012-10-01
影响因子：
6.5
通讯作者：
Arand, Michael
中科院分区：
文献类型：
--
作者：
Decker, Martina;Adamska, Magdalena;Arand, Michael
环氧化物水解酶是一个小型酶超家族，对于化学反应性外源环氧化物的解毒以及作为信号分子的内源环氧化物的加工非常重要。在这里，我们报告了两种人类环氧化物水解酶的鉴定：EH3 和 EH4。它们具有 45% 的序列同一性，因此代表了哺乳动物环氧化物水解酶的新家族。小鼠组织的定量 RT-PCR 表明 EH3 在肺、皮肤和上胃肠道中表达最强。该重组酶对 8,9-、11,12- 和 14,15-环氧二十碳三烯酸 (EET) 以及 9,10-环氧十八-11-烯酸（白细胞毒素）表现出高周转数。它被一类 N,N'-二取代脲衍生物抑制，包括 12-(3-金刚烷-1-基-脲基)-十二烷酸、1-环己基-3-十二烷基脲和 1-(1-乙酰基哌啶-4-基)-3-(4-(三氟甲氧基)苯基)脲，迄今为止的化合物 据信是哺乳动物可溶性环氧化物水解酶（sEH）的选择性抑制剂。它对 sEH 抑制剂的敏感性可能会对这些化合物的药理学特征产生影响。这是特别相关的，因为 sEH 是一个潜在的药物靶点，临床试验正在进行中，探索 sEH 抑制剂在治疗高血压和 II 型糖尿病中的价值。-Decker, M., M. Adamska, A. Cronin, F. Di Giallonardo, J. Burgener, A. Marowsky, J. R. Falck, C. Morisseau, B. D. Hammock, A. Gruzdev, D. C. Zeldin, and M·阿兰德。 EH3 (ABHD9)：新环氧化物水解酶家族的第一个成员，对脂肪酸环氧化物具有高活性。 J.脂质研究。 2012。53：2038-2045。
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.-Decker, M., M. Adamska, A. Cronin, F. Di Giallonardo, J. Burgener, A. Marowsky, J. R. Falck, C. Morisseau, B. D. Hammock, A. Gruzdev, D. C. Zeldin, and M. Arand. EH3 (ABHD9): the first member of a new epoxide hydrolase family with high activity for fatty acid epoxides. J. Lipid Res. 2012. 53: 2038-2045.