Flavin monooxygenase oxidation

Oxidative decarboxylation of hydroxybenzoates by the yeast Candida parapsilosis is catalyzed by a flavin monooxygenase that is able to use a range of fluorinated hydroxybenzoates that were examined by F NMR (Eppink et al. 1997). 

N-,0-,S-dealkylation N-, 0- or S-alkyl derivatives Flavine monooxygenases thiol compounds N-oxides... 

The flavin monooxygenases (FMOs) are a family of five enzymes (FMO 1-5) that operate in a manner analogous to the cytochrome P450 enzymes in that they oxidize the drug compound in an effort to increase its elimination. Though they possess broad substrate specificity, in general they do not play a major role in the metabolism of drugs but appear to be more involved in the metabolism of environmental chemicals and toxins. 

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. 

Two different enzyme systems have been described, one uses cytochrome P-450 to activate oxygen whereas the other employs flavin adenine dinucleotide (FAD). Both the cytochrome P-450 and the flavin monooxygenase systems have broad substrate specificities and oxidize and oxygenate a variety of organic nitrogen or sulfur compounds. The enzymes have a widespread distribution and have been detected in animals, plants, fungi and bacteria. Their function appears to be primarily one of detoxification of xenobiotics. Microbial enzymes... 

Other N-oxidized substrates include mianserin and clozapine both catalyzed by CYP1A2 and CYP3A4. Because the products are identical to those produced by flavin monooxygenases (FMOs), enzymatic studies are required to identify which enzyme system is active during in vivo metabolism. 

Abbreviations CYP, cytochrome P450 FMO, flavin monooxygenase GT, glucuronyl transferase EH, epoxide hydrolase AD, alcohol/aldehyde dehydrogenase ES/AM, esterase/amidase MT, methyl transferase ST, sulfotransferase GST, glutathione S-transferase DHD, dihydrodiol dehydrogenase COMT, catechol O-methyltransferase NA, N-actetyl transferase AA, amino acid acyltransferase P-O.P -oxidation. 

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. 

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. 

For sulfoxides/sulfides, oxidation is catalyzed by cytochrome P-450 and flavin monooxygenases, whereas the reductive metabolism is catalyzed by aldehyde oxidase and/or thiotedocin-linked enzymes. The fiver as well as the gut and bacterial flora are potential sites for the formation of sulfide metabolites. 

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