Flavin mono-oxygenase

TOBENA-SANTAMARIA, R., BLIEK, M LJUNG, K SANDBERG, G., MOL, J.N.M., SOUER, E., KOES, R., FLOOZY of petunia is a flavin mono-oxygenase-like protein required for the specification of leaf and flower architecture. Genes Dev., 2002,16, 753-763. 

Spectral studies of rapid-quench experiments indicate that the substrate/oxidized flavin/O2/reductase combination forms an initial reactive intermediate that subsequently oxygenates the substrate.30,31 These results in combination with the bonding arguments of Chapter 3 prompt the formulation in Scheme 6-7 of a general reaction mechanism for flavin mono-oxygenases. In the absence of substrate the system reduces O2 to HOOH. In either case reduction is by H-atom transfer rather than by electron transfer. 

Oxidation. Major oxidations are aromatic, aliphatic, alicyclic, heterocyclic, /V-oxidation, A-oxidation, dealkylation. Other enzymes also catalyse phase 1 reactions microsomal flavin mono-oxygenases amine oxidases, peroxidases and alcohol dehydrogenase. 

Metabolism of the dietary lipid phosphatidylcholine by gut bacteria generates trimethylamine (TMA), which is then oxidized into trimethylamine N-oxide (TMAO) by hepatic flavin mono-oxygenase (FMO). FMO expression is induced by the BA nuclear receptor FXR, upon stimulation with BA. TMAO is implicated in the formation of atherosclerotic plaque through induction of upregulation of the expression of two macrophage scavenger receptors, CD36 and SR-Al 7° Additionally TMAO were recently shown to inhibit reverse cholesterol transport (RCT),... 

Phenol o-hydroxylase is an NADPH-dependent flavin mono-oxygenase which catalyses the oxidation of phenols to o-diphenols. Wainwright described a soil enzyme assay based on the colorimetric measurement of substrate (phenol) disappearance. Soils were incubated for Ih with phenol (O.OIM) in a citrate -phosphate buffer pH 4.0 (optimum) at 37°C (temperature optimum 40-45°C). Under these conditions soil activities were linear with time and the rates of reaction were proportional to the amounts of soil. Soil activities were stimulated by Cu (purified phenol o-hydroxylase has a Cu requirement). 

Fig. 7.4.2 The origin and metabolism of TMA in man. This figure shows the molecular defect in the flavin-containing mono-oxygenase ( ) in trimethylaminuria or fish odour syndrome. The dashed line indicates the minor metabolic pathway in healthy volunteers. Enzyme steps marked with B are in the intestinal bacterial flora. DMA Dimethylamine, MMA monomethyl-...

C.T. Dolphin, A. Janmohamed, R.L. Smith, E.A. Shephard, I.R. Phillips, Missense Mutation in Flavin-containing Mono-oxygenase 3 Gene, FM03, Underlies Fish-odour Syndrome , Nat. Genet., 17, 491-494 (1997). 

Based on inhibitor studies, Wallsgrove and co-workers had been confident that at least in B. napus, flavin-containing mono-oxygenases are involved in the aldoxime formation (Bennett et al, 1993, 1995a,b Dawson et al, 1993). 

Because the 4a-flavin hydroperoxides are intermediates in both flavoprotein oxidase and mono-oxygenase chemistry/7 possible mechanisms for their formation are fundamental to an understanding of their biogenesis. 

Fig. 19.13. Cytochrome P450 mono-oxygenases. Electrons are donated by NADPH to O2 and the substrate. The flavin coenzymes FAD and FMN in one subunit transfer single electrons to cytochrome P450, which is an Fe-heme containing protein that absorbs hght at a wavelength of 450 nm. The enzyme is embedded in a membrane, usually the endoplasmic reticulum.

In addition to cytochrome P450s, hepatic microsomes contain another class of mono-oxygenases, the flavin-containing mono-oxygenases (FMO). These enzymes catalyse oxidation at nucleophilic nitrogen, sulfur and phosphorus atoms rather than oxidation at carbon atoms, e.g. for phenothiazines, ephedrine, norcocaine and the mono-ether and carbamate-containing pesticides. 

Ripp SE, Overby EIT, Phllpot RM, Elfarra AA. Oxidation of cysteine S-conjugates by rabbit liver microsomes and cDNA-expressed flavin-containing mono-oxygenases studies with S-(l,2-dichlorovinyl)-E-cysteine, S-(l,2,2 trichlorovinyl)-Ecysteine, S-allyl-E-cysteine, and S-benzyl-L-cysteine. Mol Pharmacol 1997 51 507-515. 

Dolphin, C. T., Janmohamed, A., Smith, R. L. et al. (1997) Missense mutation in flavin-containing mono-oxygenase 3 gene, FM03, underlies fish-odour syndrome. Nat Genet 17, 491-494. 

Basarab, T., Ashton, G. H., Menage, H. R et al. (1999) Sequence variations in the flavin-containing mono-oxygenase 3 gene (FM03) in fish odour syndrome. Br J Dermatol 140, 164-167. 

Oxirans.— Epoxides are readily available from the catalytic oxidation of alkenes with 2-hydroperoxyhexafluoropropan-2-ol (HPHI) (1), which itself is easily prepared from hexafluoroacetone hydrate (2) and hydrogen peroxide (Scheme 1). HPHI is claimed to have similarities to the natural flavin hydroperoxides which are implicated in epoxidations and hydroxylations by external flavoprotein mono-oxygenases. Yields are typically in the range 77—92%. 

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