Hydrolases epoxide hydrolase

Hydrolases Epoxide hydrolase Amidases and esterases Glycosidases... 

Epoxide rings of certain alkene and arene compounds are hydrated enzymatically by epoxide hydrolases to form the corresponding iram-dihydrodiols (Figure 10.11). The epoxide hydrolases are a family of enzymes known to exist both in the endoplasmic reticulum and in the cytosol. In earlier studies they were named epoxide hydratase, epoxide hydrase, or epoxide hydrolase. Epoxide hydrolase, however, has been recommended by the International Union of Biochemists Nomenclature Committee and is now in general use. 

Enzyme-catalyzed epoxide ring opening including discussion of convergent families of epoxide hydrolases, the catalytic mechanism of microsomal epoxide hydrolases, epoxide hydrolases in metabolism, and the synthesis, structure, and mechanism of leukotriene A4 hydrolase, and glutathione transferase has been reviewed by Armstrong <1999CONAP(5)51>. 

Epoxide Hydrolase. Epoxide hydrolase (EH) activity has been studied in numerous tissues with many different substrates (71-72). Hepatic microsomal EH has been shown to be induced by polycyclic aromatic hydrocarbons, but is insensitive to cytochrome P-450 type inducers (73). Epoxide hydrolase has been related to the activation of polycyclic aromatic hydrocarbons into reactive carcinogens (70). Epoxide hydrolase activity has been determined... 

Epoxide-hydrolases as asymmetric catalysts for ring opening of oxiranes 97T15617. 

For a review on epoxide hydrolases and related enzymes in the context of organic synthesis, see Faber, K. Biotransformations in Organic Chemistry, Springer New York 2004. 

Scheme 10.32 Examples of reactions catalyzed by different classes of dehalogenases. HD haloalcohol dehalogenase EH epoxide hydrolase CL p-chlorobenzoyl-CoA ligase CBD p-chlorobenzoyl-CoA dehalogenase.

The metabolism of foreign compounds (xenobiotics) often takes place in two consecutive reactions, classically referred to as phases one and two. Phase I is a functionalization of the lipophilic compound that can be used to attach a conjugate in Phase II. The conjugated product is usually sufficiently water-soluble to be excretable into the urine. The most important biotransformations of Phase I are aromatic and aliphatic hydroxylations catalyzed by cytochromes P450. Other Phase I enzymes are for example epoxide hydrolases or carboxylesterases. Typical Phase II enzymes are UDP-glucuronosyltrans-ferases, sulfotransferases, N-acetyltransferases and methyltransferases e.g. thiopurin S-methyltransferase. 

Several reports regarding the directed evolution of enantioselective epoxide hydrolases (EHs) have appeared [23,57-59]. These enzymes constitute important catalysts in synthetic organic chemistry [4,60]. The first two reported studies concern the Aspergillus niger epoxide hydrolase (ANEH) [57,58]. Initial attempts were made to enhance the enantioselectivity of the AN E H -catalyzed hydrolytic kinetic resolution of glycidyl phenyl ether (rac-19). The WT leads to an Evalue of only 4.6 in favor of (S)-20 (see Scheme 2.4) [58]. 

Figure 2.14 CASTing of the epoxide hydrolase from A. niger (ANEH) based on the X-ray structure of the WT [61]. (a) Defined randomization sites A-E (b) top view of tunnel-like binding pocket showing sites A-E (blue) and the catalytically active D192 (red) [23].

Figure 2.15 Iterative CASTing in the evolution of enantioseiective epoxide hydrolases as catalysts in the hydrolytic kinetic resolution ofrac-19[23].

Furstoss et al. have reported their studies on the use of an epoxide hydrolase with four styrene oxide derivatives (Figure 5.26) [39]. The (R)-diol (43) was obtained in 91% ee at 100% conversion from racemic (42), demonstrating an enantioconvergent... 

Figure 5.25 Enantioconvergent hydrolysis of epoxides (35) to the corresponding diols (36) using mung bean epoxide hydrolase.

Chiral epoxides and their corresponding vicinal diols are very important intermediates in asymmetric synthesis [163]. Chiral nonracemic epoxides can be obtained through asymmetric epoxidation using either chemical catalysts [164] or enzymes [165-167]. Biocatalytic epoxidations require sophisticated techniques and have thus far found limited application. An alternative approach is the asymmetric hydrolysis of racemic or meso-epoxides using transition-metal catalysts [168] or biocatalysts [169-174]. Epoxide hydrolases (EHs) (EC 3.3.2.3) catalyze the conversion of epoxides to their corresponding vicinal diols. EHs are cofactor-independent enzymes that are almost ubiquitous in nature. They are usually employed as whole cells or crude... 

Epoxide hydrolases hydrate epoxides to yield transdihydrodiols without any requirement for cofactors. Examples are given in Figure 2.12. Epoxide hydrolases are... 

The microsomal fraction consists mainly of vesicles (microsomes) derived from the endoplasmic reticulum (smooth and rough). It contains cytochrome P450 and NADPH/cytochrome P450 reductase (collectively the microsomal monooxygenase system), carboxylesterases, A-esterases, epoxide hydrolases, glucuronyl transferases, and other enzymes that metabolize xenobiotics. The 105,000 g supernatant contains soluble enzymes such as glutathione-5-trans-ferases, sulfotransferases, and certain esterases. The 11,000 g supernatant contains all of the types of enzyme listed earlier. 

Emphasis is given to the critical role of metabolism, both detoxication and activation, in determining toxicity. The principal enzymes involved are described, including monooxygenases, esterases, epoxide hydrolases, glutathione-5 -transferases, and glucuronyl transferases. Attention is given to the influence of enzyme induction and enzyme inhibition on toxicity. 

In the rabbit, the nonplanar PCB 2,2, 5,5 -tetrachlorobiphenyl (2,2, 5,5 -TCB) is converted into the 3, 4 -epoxide by monooxygenase attack on the meta-para position, and rearrangement yields two monohydroxymetabolites with substitution in the meta and para positions (Sundstrom et al. 1976). The epoxide is also transformed into a dihydrodiol by epoxide hydrolase attack (see Chapter 2, Section 2.3.2.4). This latter conversion is inhibited by 3,3,3-trichloropropene-l,2-oxide (TCPO), thus providing strong confirmatory evidence for the formation of an unstable epoxide in the primary oxidative attack (Forgue et al. 1980). 

Epoxide hydrolase A type of enzyme that converts epoxides to diols by the addition of water. 

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