Flavin monooxygenase enzymes

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. 

Upon ingestion, PAs are absorbed mainly through the small intestine and are carried to the liver. The most hydrophobic PAs are readily excreted unchanged in the urine within a 24 h period while less hydrophobic PAs are metabolized by cytochrome P450s and flavin monooxygenase enzymes. The metabolites are eliminated as soluble glutathione and other conjugates in the bile and urine. 

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. 

The straightforward concept for the direct light-driven regeneration of flavin-dependent enzymes has been successfully applied for two representative classes of such enzymes a reductase and a monooxygenase. Therefore, it can be expected that this concept can also be applied to other flavin-dependent enzymes, potentially leading to additional practical catalyst systems for applications in synthetic organic chemistry. 

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. 

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

Ziegler DM (1990) Flavin-containing monooxygenases enzymes adapted for multisubstrate specificity. Trends Pharmacol Sci 11 321-324... 

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... 

Figure 3 Illustration of possible partial reaction cycles of some oxygenase enzymes. Water molecules and protein ligands have sometimes been omitted for clarity, (a) P450 (18) (b) intradiol dioxygenase (7) (c) lipoxygenase (7) (d) a-KG-dependent non-heme Iron enzymes (14) (e) soluble methane monooxygenase (15) (f) uncoupled blnuclear copper (16) (g) coupled blnuclear copper (h) flavin monooxygenases (17).

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. 

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