Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism.
Flavin-containing monooxygenase (FMO) oxygenates drugs and xenobiotics containing a "soft-nucleophile", usually nitrogen or sulfur. FMO, like cytochrome P450 (CYP), is a monooxygenase, utilizing the reducing equivalents of NADPH to reduce 1 atom of molecular oxygen to water, while the other atom is used to oxidize the substrate. FMO and CYP also exhibit similar tissue and cellular location, molecular weight, substrate specificity, and exist as multiple enzymes under developmental control. The human FMO functional gene family is much smaller (5 families each with a single member) than CYP. FMO does not require a reductase to transfer electrons from NADPH and the catalytic cycle of the 2 monooxygenases is strikingly different. Another distinction is the lack of induction of FMOs by xenobiotics. In general, CYP is the major contributor to oxidative xenobiotic metabolism. However, FMO activity may be of significance in a number of cases and should not be overlooked. FMO and CYP have overlapping substrate specificities, but often yield distinct metabolites with potentially significant toxicological/pharmacological consequences. The physiological function(s) of FMO are poorly understood. Three of the 5 expressed human FMO genes, FMO1, FMO2 and FMO3, exhibit genetic polymorphisms. The most studied of these is FMO3 (adult human liver) in which mutant alleles contribute to the disease known as trimethylaminuria. The consequences of these FMO genetic polymorphisms in drug metabolism and human health are areas of research requiring further exploration.
Krueger
Sharon K
SK
Department of Environmental and Molecular Toxicology and The Linus Pauling Institute, Oregon State University, USA.
Williams
David E
DE
D000595:Amino Acid Sequence; D000818:Animals; D006801:Humans; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010105:Oxygenases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D011110:Polymorphism, Genetic; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D004364:Pharmaceutical Preparations; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming)