Discovery of inhibitors of soluble epoxide hydrolase: a target with multiple potential therapeutic indications.
Discovery of inhibitors of soluble epoxide hydrolase: a target with multiple potential therapeutic indications.
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DOI：
10.1021/jm201468j
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发表时间：
2012-03-08
影响因子：
7.3
通讯作者：
Hammock, Bruce D.
中科院分区：
文献类型：
--
作者：
Shen, Hong C.;Hammock, Bruce D.
1.前言环氧化物水解酶已在从植物到哺乳动物的原核生物和真核生物中检测到。1− 3在哺乳动物中，包括可溶性环氧化物水解酶（sEH）、微粒体环氧化物水解酶（mEH）、胆固醇环氧化物水解酶和白三烯A4（LTA 4）水解酶。这些酶介导的水添加到外源性和内源性的环氧化物，导致相应的邻位二醇除了LTA 4水解酶，它们显示出不同的底物选择性。例如，哺乳动物sEH对脂肪族环氧化物，特别是脂肪酸环氧化物具有选择性，而mEH对环状和芳烃环氧化物更具选择性。对mEH的研究重点是其在异生物质代谢中的作用，但其分布，特别是在大脑和肾上腺中的分布，表明可能存在内源性作用。4虽然它对脂肪酸环氧化物的催化活性很低，但某些脑区的高水平mEH可能有助于它们的水解。sEH对芳烃氧化物和其他环状环氧化物的催化活性如此之低，以至于与mEH以及化学和谷胱甘肽S-转移酶催化的反应性环氧化物的缀合相比，其贡献显得微不足道。虽然sEH可以代谢一些脂肪族天然产物，但sEH被认为主要参与调节性环氧脂质的代谢，特别是花生四烯酸级联的那些（图1）。游离花生四烯酸的滴度非常低，但当它被释放时，它被转化为各种各样的生物活性代谢物。大多数研究集中在环氧合酶和脂氧合酶途径，但越来越多的注意力被支付给细胞色素P450的级联分支。一组P450酶进行烯丙基和ω和ω-1氧化。另一组P450酶形成花生四烯酸和其他不饱和脂质的区域异构环氧化物。在花生四烯酸系列中，这些环氧化物被称为环氧二十碳三烯酸（ESTs）。雌二醇通过掺入磷脂、链缩短、链延长、羟基化和其他途径代谢。5然而，主要途径是通过sEH将环氧化物水合为相应的1，2-二醇。值得注意的是，已经发现多种药物作用于花生四烯酸代谢级联的环氧合酶和脂氧合酶分支。例如，许多非甾体抗炎药（NSAID）是环氧合酶-1（考克斯-1）和环氧合酶-2（考克斯-2）的抑制剂。6此外，孟鲁司特是一种白三烯（LT）受体拮抗剂，可阻断LTD 4和二级配体LTC 4和LTE 4的作用。7齐留通抑制5-脂氧合酶，这是一种用于产生LT的类二十烷酸合成途径的酶。8孟鲁司特和齐留通都是治疗哮喘的有效疗法。最后，将前列腺素D2的DP 1受体拮抗剂laropiprant与烟酸联合使用，以抑制烟酸诱导的血管舒张。9如图2所示，人sEH（hsEH，EPHX 2，EC 3.3. 2.10）是位于细胞溶质和过氧化物酶体中的双功能同源二聚体酶，具有环氧化物水解酶和磷酸酶活性。具体地，sEH的C-末端环氧化物水解酶基序将Escherichia coli的四种区域异构体，即5，6-、8，9-、11，12-和14，15-Escherichia coli转化为相应的二羟基二十碳三烯酸（DHEscherichia coli），其中Escherichia coli是通过细胞色素P450环氧合酶从花生四烯酸衍生的内源性化学介质，由此Escherichia coli的生物学效应被减弱、消除，或者被改变了10最近的研究表明，一些脂肪酸二醇具有...
1. INTRODUCTION Epoxide hydrolases have been detected in prokaryotes and eukaryotes ranging from plants to mammals. 1− 3 In mammals these include the soluble epoxide hydrolase (sEH), microsomal epoxide hydrolase (mEH), cholesterol epoxide hydrolase, and leukotriene A4 (LTA4) hydrolase. These enzymes mediate the addition of water to both exogenous and endogenous epoxides, leading to the corresponding vicinal diols except for LTA4 hydrolase, and they display different substrate selectivity. For example, the mammalian sEH is selective for aliphatic epoxides and particularly fatty acid epoxides, whereas mEH is more selective for cyclic and arene epoxides. Studies on the mEH have focused on its role in xenobiotic metabolism, but its distribution, particularly in the brain and adrenal gland, suggests a possible endogenous role. 4 Although its catalytic activity on fatty acid epoxides is low, the high level of the mEH in some brain regions may contribute to their hydrolysis. The catalytic activity of the sEH on arene oxides and other cyclic epoxides is so low that its contribution appears insignificant compared to the mEH as well as for chemical and glutathione S-transferase catalyzed conjugation of reactive epoxides. Although the sEH can metabolize some aliphatic natural products, the sEH is thought to be involved largely in the metabolism of regulatory epoxy lipids, particularly those of the arachidonic acid cascade (Figure 1). Titers of free arachidonic acid are very low, but when it is released, it is converted to a wide variety of biologically active metabolites. Most research has focused on the cyclooxygenase and lipoxygenase pathways, but increasing attention is being paid to the cytochrome P450 branch of the cascade. One set of P450 enzymes carry out allylic and ω and ω-1 oxidation. Another set of P450 enzymes form regioisomeric epoxides of arachidonic acid and other unsaturated lipids. In the arachidonate series these epoxides are called epoxyeicosatrienoic acids (EETs). The EETs are metabolized by incorporation into phospholipids, chain shortening, chain elongation, hydroxylation, and other pathways. 5 However, the dominant pathway is hydration of the epoxides to the corresponding 1, 2-diols by sEH. It is noted that multiple drugs have already been discovered to act on the cyclooxygenase and lipoxygenase branches of the arachidonic acid metabolic cascade. For example, numerous nonsteroidal antiinflammatory drugs (NSAIDs) are inhibitors of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). 6 In addition, montelukast is a leukotriene (LT) receptor antagonist blocking the action of LTD4 and secondary ligands LTC4 and LTE4. 7 Zileuton inhibits 5-lipoxygenase, an enzyme of the eicosanoid synthesis pathway for the production of LTs. 8 Both montelukast and zileuton are effective therapies for treatment of asthma. Lastly, laropiprant, an antagonist of the DP1 receptor of prostaglandin D2, is used in combination with niacin to suppress the niacin-induced vasodilation. 9As shown in Figure 2, sEH in human (hsEH, EPHX2, EC 3.3. 2.10) is a bifunctional homodimeric enzyme located in both cytosol and peroxisomes with both epoxide hydrolase and phosphatase activity. 1 Specifically, the C-terminus epoxide hydrolase motif of sEH transforms four regioisomers of EETs, namely, 5, 6-, 8, 9-, 11, 12-, and 14, 15-EETs, which are the endogenous chemical mediators derived from arachidonic acid by cytochrome P450 epoxygenases, to the corresponding dihydroxyeicosatrienoic acids (DHETs), whereby the biological effects of EETs are diminished, eliminated, or altered. 10 Recent work has shown that some fatty acid diols have …
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影响因子：
8.3
作者：
Corenblum, Mandi J.;Wise, Vance E.;Fornage, Myriam
通讯作者：
Fornage, Myriam
影响因子：
2.9
作者：
Chen, Dawn;Whitcomb, Randall;Webb, Heather K.
通讯作者：
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影响因子：
2.7
作者：
Anandan, Sampath-Kumar;Webb, Heather K.;Gless, Richard D.
通讯作者：
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影响因子：
20.1
作者：
Campbell, WB;Gebremedhin, D;Harder, DR
通讯作者：
Harder, DR
影响因子：
3
作者：
Dorrance, AM;Rupp, N;Imig, JD
通讯作者：
Imig, JD