Epoxide hydroxylases

Omiecinski CJ. Epoxide hydroxylases. In Levy RH, Thummel KE, Trager WF, et al., eds. Metabolic Drug Interactions. Philadelphia, PA Lippincott, Williams Wilkins 2000. 

Epoxide hydrolase (EC 33.23) activity in pulmonary alveolar macrophages obtained from 11 patients by bronchoalveolar lavage was 0.241 0.10 nmol/ min x mg protein (Petruzzelli et al. 1988). Epoxide hydroxylase activity was 0.161 0.02 nmol/min x mg protein in non-smokers and 0.3110.08 nmol/ min x mg protein in smokers (P <0.001). 

Anticancer drug resistance may be due to the expression of cytochromes P450 (Guengerich 1988), epoxide hydroxylase, and glutathione S-transferase (Harrison 1993, 1995). 

This epoxide is further metabolized by the enzyme epoxide hydroxylase to form a trans diol, which undergoes glucuronidation to produce a water-soluble adduct that can be excreted in the urine. 

The epoxide metabolite is believed to exhibit activity similar to that of the parent compound and therefore contributes substantially to the overall therapeutic effects of carbamazepine. This feet must be taken into consideration when a patient is taking other medications. For instance, the antibiotic clarithromycin has been found to inhibit the action of the enzyme epoxide hydroxylase. This causes the concentration of the epoxide to be higher than normal, increasing the potency of carbamazepine. Before a physician prescribes carbamazepine for a patient, potential drug interactions must be taken into account This is an example of one important factor that practicing physicians must consider—specifically, the effect that one drug can have on the potency of another drug. 

The alkane hydroxylase from Pseudomonas oleovorans is particularly suitable for the epoxidation of terminal aliphatic double bonds and enables rapid access to the (3-blocker metoprolol (Scheme 9.14) [113,116]. Complementing this regioselectivity, chloroperoxidases are particularly suitable biocatalysts for the epoxidation of (ds substituted) subterminal olefins [112,117]. This enzyme also accepts terminal olefins and is utilized for the effident synthesis of P-mevalono-ladone [118]. 

Epoxides may be formed from alkenes during degradation by Pseudomonas oleovorans, although octan-l,2-epoxide is not further transformed, and degradation of oct-l-ene takes place by co-oxidation (May and Abbott 1973 Abbott and Hou 1973). The co-hydroxylase enzyme is able to carry out either hydroxylation or epoxidation (Ruettinger et al. 1977). 

Such an attack could lead in step a either to an epoxide (arene oxide) or directly to a carbocation as shown in Eq. 18-47. Arene oxides can be converted, via the carbocation step b, to end products in which the NIH shift has occurred.438 The fact that phenylalanine hydroxylase also catalyzes the conversion of the special substrate shown in Eq. 18-48 to a stable epoxide, which cannot readily undergo ring opening, also supports this mechanism. 

Pseudomonas oleovorans contains P. oleovorans monooxygenase (POM), which is a typical co-hydroxylase for hydroxylation of the terminal methyl of alkanes as well as epoxidation of terminal olefins. The co-hydroxylation system of P. oleovorans was reconstituted from purified components, POM, rubredoxin, and a flavoprotein reductase [122], In the presence of NADH and oxygen, it oxidizes a wide range of aliphatic methyl alkyl sulfides. Enantioselectivities are very much dependent of the length of the alkyl chain of Me-S(0)-R, as exemplified by the following results ... 

This mechanism is consistent with a number of observations. Kinetic studies on prolyl 4-hydroxylase [223] and thymine hydroxylase (EC 1.14.11.6) [224] suggest that cofactor binds first, followed by 02. The bound 02 appears to have superoxide character, as superoxide scavengers are competitive inhibitors of 02 consumption [225,226], It is also clear that the oxidative decarboxylation of the keto acid is a distinct phase of the mechanism from the alkane functionalization step, as these two phases can be uncoupled, particularly when poor substrate analogs are employed [227-229], Evidence for an Fe(IV) = 0 intermediate derives from studies with substrate analogs. Besides the hydroxylation of the 5-methyl group of thymine, thymine hydroxylase can also catalyze ally lie hydrox-ylations, epoxidation of olefins, oxidation of sulfides to sulfoxides, and N-de-... 

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