Flavin Monooxygenases: A Multifaceted Class of Enzymes with Abundant Biomedical Applications

Abstract

Flavin-dependent monooxygenases (FMOs) catalyze oxidation of a variety of organic molecules many of which have a profound biomedical applications. Oxidation occurs through the incorporation of a single atom of dioxygen into the substrate while the other oxygen atom is reduced to water. Since 2014, FMOs are grouped into eight types listed as Groups A through H. Grouping is based on structural homology, flavin type and the strategy taken to reduce the isoalloxazine ring of the cofactor for subsequent oxygen activation and substrate monooxygenation. Groups A and B FMOs are single component enzymes that carry out their entire reaction cycle in a single protein core using a nicotinamide adenine dinucleotide coenzyme as electron source. Groups C through F are two comments FMOs. These systems contain a reductase to reduce the flavin cofactor that is then delivered to a monooxygenase component as a substrate. Reduced flavin then activates molecular oxygen in the second component to oxidize the organic metabolite of the system. Finally, Groups G and H are self- sufficient internal monooxygenases that receive electrons from one substrate for the oxidation of a second one all within a single protein unit. FMOs carry out an array of biomedically relevant reactions including the degradation of antibiotics by pathogens, the biocatalytic production of drugs in pharmaceutical industries and cholesterol anabolism in humans and fungi. Given this diversity of both reaction type and application, the field of FMO enzymology can rapidly become overwhelming. This review provides a general overview of each FMO group and is intended to guide researchers just entering the field. Canonical enzymes are detailed along with biomedically important members of each group. It is hoped the references herein will be provide a quick source to make more extensive literature reviews more accessible.