5.05.2.2 Flavin Monooxygenases
5.05.2.2.1 Occurrence, multiplicity, catalytic cycle, oxygen activation, and selectivity
The oxidative activity of the NADPH and O2-dependent FMOs are largely complementary to that of the cytochromes P450.152 Like the cytochromes P450, the FMOs are widely distributed in nature, have multiple family members, with six (FMO1-FMO6) having been characterized.153 In humans they are found in close association with cytochrome P450 in the endoplasmic reticulum of most tissues, with the greatest concentration being in liver (FMO3)154'155 FMO1 is the major form in human fetal liver,156 but it localizes in the kidney in the adult.157 The FMOs display broad substrate selectivity, and like cytochrome P450 the primary criterion for reaction is substrate access to the active oxidizing
152,158 species. 2
Unlike the cytochromes P450 the FMOs appear not to be inducible, and operate by the two-electron oxidation characteristic of peroxides. Nature seems to have designed the FMOs to be selective for a class of compounds that the cytochromes P450 are less efficient at oxidizing: xenobiotics that contain electron-rich polarizable nucleophilic groups. These are largely compounds containing the elements sulfur, nitrogen, selenium, and phosphorus (thiols, sulfides, disulfides, amines (1°, 2°, and 3°), imines, hydrazines, hydroxylamines, selenols, selenides, phosphines, etc.).152
The active oxygen species utilized by the FMOs is the C(4a)-hydroperoxyflavin 136, generated from O2 addition to FADH2, formed upon reduction of flavin adenine dinucleotide (FAD) by enzyme-bound NADPH (Figure 5). The substrate is oxidized, water eliminated from the residual C(4a)-hydroxyflavin, and FAD regenerated to complete the catalytic cycle.159-161
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