Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism

This 2005 review is an excellent reference paper on the human flavin-mono-oxygenase enzyme family, particularly the most active form of FMO in humans, FMO3. It can probably be regarded as the current defining article on FMO (especially FMO3), or at least the defining free version. It was written by Williams and Krueger of the Linus Pauling institute, who can probably be regarded as 2 of the few FMO experts in the world. FMO3 is the enzyme regarded as being at fault in cases of Primary Trimethylaminuria. The full paper can be read via the link.

Abstract:

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.

Full paper (2005): Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism