Properties of liver microsomal cholesterol 5,6-oxide hydrolase

Nashed, Nashaat T.; Michaud, Dennis P.; Levin, Wayne; Jerina, Donald M.

doi:10.1016/0003-9861(85)90371-6

Cited by 31 publications

(15 citation statements)

References 50 publications

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“…Several imino compounds are competitive inhibitors for the enzyme from rat liver. The most effective of these is 5,6 a-iminocholestanol (K i =0.085 mM) [1]. Inhibition by aziridines is consistent with the participation of acid catalysis in the mechanism of action of the enzyme [1].…”

Section: Substrates and Inhibitorsmentioning

confidence: 53%

“…The most effective of these is 5,6 a-iminocholestanol (K i =0.085 mM) [1]. Inhibition by aziridines is consistent with the participation of acid catalysis in the mechanism of action of the enzyme [1]. Other inhibitors that have been characterized including the inhibitors 7-ketocholesterol, 6-ketocholestanol, and 7-ketocholestanol, with the latter displaying an apparent K i lower than the K m for either cholesterol epoxide isomer.…”

Section: Substrates and Inhibitorsmentioning

confidence: 71%

“…As indicated previously, cholesterol oxide hydrolase is a distinct enzyme from oxidosqualene cyclase, as well as from microsomal epoxide hydrolase, the latter being responsible for the metabolism of a wide range of xenobiotic alkene and arene oxides [4,1,5]. Although the cholesterol 5,6 b-oxide is more reactive than the a-oxide upon acid-catalyzed hydration, the a-oxide is a 4.5-fold better substrate than the b-oxide as indicated by values of V max /K m [1].…”

Section: Substrates and Inhibitorsmentioning

confidence: 83%

“…Although the cholesterol 5,6 b-oxide is more reactive than the a-oxide upon acid-catalyzed hydration, the a-oxide is a 4.5-fold better substrate than the b-oxide as indicated by values of V max /K m [1]. The enzyme activity of both 5,6 a-and 5,6 b-oxide diastereomers is product-inhibited by cholestanetriol through a competitive mechanism with the apparent K i for cholestanetriol being 10.8 and 6.8 mM against cholesterol a-and b-epoxides, respectively [6].…”

Section: Substrates and Inhibitorsmentioning

confidence: 99%

“…1) to cholestane 3 b, 5 a, 6 b-triol is catalyzed by cholesterol oxide hydrolase, a microsomal hydrolase found in mammalian liver tissues. The gene or cDNA encoding this protein has yet to be cloned or characterized, but is distinct from oxidosqualene cyclase [1]. Cholesterol epoxide hydrolase displays a wide tissue distribution with all tissues tested showing cholesterol epoxide hydrolase activity [2].…”

Section: Introductionmentioning

confidence: 99%

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Epoxide hydrolases: biochemistry and molecular biology

Fretland

Omiecinski

2000

Chemico-Biological Interactions

273

185

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Epoxides are organic three-membered oxygen compounds that arise from oxidative metabolism of endogenous, as well as xenobiotic compounds via chemical and enzymatic oxidation processes, including the cytochrome P450 monooxygenase system. The resultant epoxides are typically unstable in aqueous environments and chemically reactive. Biol. Chem. 260 (1985) 1630-1640). Therefore, it is of vital importance for the biological organism to regulate levels of these reactive species. The epoxide hydrolases (E.C. 3.3.2.3) belong to a sub-category of a broad group of hydrolytic enzymes that include esterases, proteases, dehalogenases, and lipases Beetham et al. (DNA Cell Biol. 14 (1995) 61 -71). In particular, the epoxide hydrolases are a class of proteins that catalyze the hydration of chemically reactive epoxides to their corresponding dihydrodiol products. Simple epoxides are hydrated to their corresponding vicinal dihydrodiols, and arene oxides to trans-dihydrodiols. In general, this hydration leads to more stable and less reactive intermediates, however exceptions do exist. In mammalian species, there are at least five epoxide hydrolase forms, microsomal cholesterol 5,6-oxide hydrolase, hepoxilin A 3 hydrolase, leukotriene A 4 hydrolase, soluble, and microsomal epoxide hydrolase. Each of these enzymes is distinct chemically and immunologically. Table 1 illustrates some general properties for each of these classes of hydrolases. Fig. 1 provides an overview of selected model substrates for each class of epoxide hydrolase.

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Section: Substrates and Inhibitorsmentioning

confidence: 53%

Section: Substrates and Inhibitorsmentioning

confidence: 71%

Section: Substrates and Inhibitorsmentioning

confidence: 83%

Section: Substrates and Inhibitorsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Epoxide hydrolases: biochemistry and molecular biology

Fretland

Omiecinski

2000

Chemico-Biological Interactions

273

185

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Epoxide Hydrolases

Omiecinski¹,

Yang²,

Laurenzana³

2012

Encyclopedia of Drug Metabolism and Interactions

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Epoxides are three‐membered carbon–oxygen compounds that typically arise from the metabolism of endogenous and xenobiotic compounds via chemical and enzymatic oxidation processes. Many different oxygenase enzymes are capable of forming epoxide derivates, from either arene or alkene substrate; however, the cytochrome P450 monooxygenases are principal contributors to their generation. Certain epoxides are highly electrophilic and chemically reactive, and they have been implicated as initiators of various cellular toxicities, including the formation of DNA mutations and ultimately, cancers. Therefore, it is of vital importance for the organism to regulate levels of these reactive species. A single mammalian enzyme, microsomal epoxide hydrolase (EPHX1, mEH), functions as a predominant pathway responsible for detoxification of xenobiotic epoxides, as well as bioactivation pathway for certain xenobiotic epoxides. In contrast, another important epoxide hydrolase, soluble epoxide hydrolase (EPHX2, sEH), has more recently been established as a mediator of epoxide hydrolysis of several endogenously derived epoxyeicosatrienoic acids (EETs), intermediates resulting from arachidonic acid metabolism. In this respect, EPHX2 is now characterized as an important regulator of physiological processes, such as blood pressure and inflammation, and has emerged as a promising therapeutic target for pharmacological intervention. This chapter reviews the biochemistry, biological regulation, genetics, and pharmacological relevance of these important enzyme systems.

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