FMOs

FMOs, or flavin-containing monooxygenases, are a family of NADPH-dependent, FAD-containing enzymes that catalyze oxidative metabolism of a broad range of soft nucleophiles, notably nitrogen- and sulfur-containing compounds, as well as certain heteroatoms and some carbon substrates found in drugs and endogenous molecules. They transfer one atom of molecular oxygen to the substrate while reducing the other to water, using NADPH as the electron donor. The catalytic cycle involves a reduced flavin cofactor reacting with O2 to form a hydroperoxyflavin intermediate that transfers oxygen to the substrate, generating products such as N-oxides, S-oxides, or hydroxylated compounds. Substrate scope and regiospecificity depend on the specific FMO isoform.

In humans, the FMO family comprises several genes with tissue-specific expression. The best characterized is FMO3, which is highly expressed in adult liver and is responsible for the major pathway of trimethylamine oxidation to trimethylamine N-oxide; loss of FMO3 activity causes trimethylaminuria, a condition associated with a distinctive fish-like odor. Other FMOs, including FMO1, FMO2, FMO4, and FMO5, are expressed in different tissues and developmental stages and contribute to the metabolism of a variety of substrates. Genetic variation in these enzymes can influence individual metabolic profiles.

Clinical and research relevance: Polymorphisms in FMO genes contribute to interindividual differences in drug and xenobiotic metabolism. FMOs participate in detoxification processes for dietary components and environmental chemicals and can modulate susceptibility to certain toxicants. Compared with cytochrome P450s, FMOs are less broadly inducible but still show variability due to genetics, development, and physiological state.

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