Monooxygenases flavin

The carbamate insecticide aldicarb (Figure 2.13) that exerts its effect by inactivating acetylcholinesterase is metabolized by a flavin monooxygenase from rainbow trout to the sulfoxide, which is a more effective inhibitor (Schlenk and Buhler 1991). 

Vannelli TA, A Dykman, PR Ortiz de Montellano (2002) The antituberculosis drug ethionamide is activated by a flavin monooxygenase. J Biol Chem 277 12824-12829. 

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). 

ZHAO, Y., CHRISTERSEN, S.K., FANKHAUSER, C., CASHMAN, J., COHEN, J., WEIGEL, D., CHORY, J., A role for flavin monooxygenase-like enzymes in auxin biosynthesis, Science, 2001, 291, 306-309. 

Reid JM, Walker DL, Miller JK, et al. The metabolism of pyrazoloacridine (NSC 366140) by cytochromes p450 and flavin monooxygenase in human liver microsomes. Clin Cancer Res 2004 10(4) 1471-1480. 

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

Baeyer-Villiger reaction Aldehyde, ketones Flavine monooxygenase Esters, lactones... 

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. 

Foster BC, Sockovie ER, Bellefeuille NC, et al. Effect of St. John s wort on cytochrome P-450 and flavin monooxygenase enzymes and on P-glycoprotein. Can J Infect Dis 2001 12(suppl B) 132P. 

Flavin monooxygenase (Ziegler s enzyme) H+ R3N R3N — R3N OH Chlorpromazine, amitriptyline, benzphetamine... 

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. 

Tire tetrahydrobiopterin formed in this reaction is similar in structure to a reduced flavin. The mechanism of its interaction with 02 could reasonably be the same as that of 4-hydroxybenzoate hydroxylase. However, phenylalanine hydroxylase, which catalyzes the formation of tyrosine (Eq. 18-45), a dimer of 451-residue subunits, contains one Fe per subunit,113 313i whereas flavin monooxygenases are devoid of iron. Tyrosine hydroxylase416 193 and tryptophan hydroxylase420 have very similar properties. All three enzymes contain regulatory, catalytic, and tetramerization domains as well as a common Fe-binding motif in their active sites.413 421 4213... 

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... 

Scheme 2.1 F = flavin monooxygenase cofactor = methyl carbon of acetate precursor...

Figure 18 Effect of nonionic detergent (Triton X-100) on benzydamine N-oxygenation (FMO) and N-demethylation (CYP) by human liver microsomes. Benzydamine (500 pM) was incubated with pooled human liver microsomes (1.0 mg protein/mL) in tricine buffer (50 mM, pH 8.5 at 37°C) with or without Triton X-100 [1% (v/v)]. Reactions were initiated by the addition of an NADPH-generating system and stopped after 10 minute by the addition of an equal volume (500 pL) of methanol. Precipitated protein was removed by centrifugation, and an aliquot (25 pL) of the supernatant fraction was analyzed by HPLC with fluorescence detection. Abbreviations FMO, flavin monooxygenase CYP, cytochrome P450.

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