Epoxide hydrolases: biochemistry and molecular biology

Epoxides are organic three-membered oxygen compounds that arise from oxidat ive metabolism of endogenous, as well as xenobiotic compounds via chemical and enzymatic oxidation processes, including the cytochrome P450 monooxygen ase system. The resultant epoxides are typically unstable in aqueous enviro nments and chemically reactive. In the case of xenobiotics and certain endo genous substances, epoxide intermediates have been implicated as ultimate m utagenic and carcinogenic initiators Adams et al. (Chem. Biol. Interact. 95 (1995) 57-77) Guengrich (Properties and Metabolic roles 4 (1982) 5-30) Say er et al. (J. 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, deh alogenases, and lipases Beetham ct al. (DNA Cell Biol. 14 (1995) 61-71). In particular, the epoxide hydrolases are a class of proteins that catalyze t he hydration of chemically reactive epoxides to their corresponding dihydro diol products. Simple epoxides are hydrated to their corresponding vicinal dihydrodiols, and arene oxides to trans-dihydrodiols. In general, this hydr ation leads to more stable and less reactive intermediates, however excepti ons do exist. In mammalian species, there are at least five epoxide hydrola se forms, microsomal cholesterol 5,6-oxide hydrolase, hepoxilin A(3) hydrol ase, 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 o f epoxide hydrolase. (C) 2000 Elsevier Science Ireland Ltd. All rights rese rved.