Oxidative reactions flavin monooxygenases

Major oxidations are aromatic, aliphatic, alicyclic, heterocyclic, N-oxidation, S-oxidation, dealkylation. Other enzymes also catalyze phase 1 reactions microsomal flavin monooxygenases, amine oxidases, peroxidases, and alcohol dehydrogenase. 

Enzymes that catalyze the Baeyer-Villiger reaction are a subset of the flavin monooxygenases. In the mechanism of oxidation catalyzed by such enzymes one atom of molecular oxygen is incorporated into the substrate, whereas the other is reduced to H20. Two cofactors are required for catalytic activity. The first is a reduced flavin (FAD or FMN) bound non-covalently in the active site. The riboflavin moiety of flavin monooxygenase holoproteins is shown in Fig. 16.5-15 the second is a reduced nicotinamide cofactor (NADPH or NADH), which is required to furnish the enzyme with electrons to reduce the flavin. 

A few other oxidation reactions have been reported in helminths. The cytosolic fractions of Moniezia expansa and Ascaris suum catalyze the sulfoxidation of several xenobiotics, including the benzimidazole derivatives albendazole and fenbendazole, to the corresponding sulfoxides (10). The reaction requires NADPH and molecular oxygen, but unlike mammalian sulfoxidase, it is not associated with the microsomal fraction. Although parasite sulfoxidases have not been purified, their properties suggest they are soluble forms of flavin-linked monooxygenase. 

Flavine monooxygenases. Flavine monooxygenases (FMO) are a family of microsomal flavoproteins that catalyse the oxidation of numerous organic or inorganic compounds, including various strucmrally unrelated xenobiotics, in the presence of NADPH and oxygen. As for cytochrome P450, FMO are involved in detoxication and toxication reactions. 

Figure 1.47 Flavin-dependent Baeyer-Villiger monooxygenase-mediated oxidation reactions.

Oxidations are the most common biotransformation reactions that occur with most drugs. There are several classes of enzymes that carry out these reactions cytochrome P450s, flavin monooxygenases, monoamine oxidases, xanthine oxidase, aldehyde oxidases, aldehyde dehydrogenases, and peroxidases. Typical reactions and substrate substructures for each of these classes of enzymes will be described. 

As the flavin-dependent enzyme, a mutant of phenylacetone monooxygenase, PAMO-P3, was chosen [104], which had previously been engineered to catalyze the enantioselective BV reaction of substituted ketones. The unnatural regeneration conditions did not impair the inherent stereoselectivity of PAMO-P3, suggesting an unaltered mechanism of the actual oxidation reaction. The present light-driven BV reaction is expected to work just as well using other flavin-dependent BVMOs such as CHMO, which accepts a broader range of substrates. 

The enzyme in Rhodococcus sp. strain IGTS8 that brings about successive oxidation of dibenzothiophene to the sulfoxide and the sulfone is a flavin mononucleotide-dependent monooxygenase that carries out both reactions by sequential incorporation of a single atom of oxygen from Oj (Lei and Tu 1996). 

In flavin-dependent monooxygenases, a flavin-oxygen intermediate reacts with the substrate, also producing water in a second step, and requiring cofactors for regeneration of the flavin moiety. The unusual flavoprotein vanillyl-alcohol oxidase (EC 1.1.3.38), in which the flavin moiety is covalently bound, catalyzes the oxidation of p-substituted phenols as well as deamination, hydroxylation and dehydrogenation reactions [10]. 

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