Abstract
Flavoprotein monooxygenases (FPMOs) exhibit an array of mechanistic solutions to a common chemical objective; the monooxygenation of a target substrate. Each FPMO efficiently couples reduction of a flavin cofactor by NAD(P)H to oxygenation of the target substrate via a (hydro)peroxyflavin intermediate. This purpose of this review is to describe in detail the Class A flavoprotein hydroxylases (FPMO) in the context of the other FPMO classes (B–F). Both one and two component FPMOs are found in nature. Two-component enzymes require, in addition to the monooxygenase, the involvement of a reductase that first catalyzes the reduction of the flavin by NAD(P)H. The Class A and B FPMOs are single-component and manage to orchestrate the same net reaction within a single peptide. The Class A enzymes have, by some considerable margin, the most complete research record. These enzymes use choreographed movements of the flavin ring that facilitate access of the organic substrates to the active site, provide a means for interaction of NADPH with the flavin, offer a mechanism to sequester the dioxygen reduction chemistry from solvent and a means to release the product. The majority of the discrete catalytic events of the catalytic cycle can be observed directly in exquisite detail using spectrophotometric kinetic methods and many of the key mechanistic conclusions are further supported by structural data. This review attempts to compile each of the key observations made for both paradigm and newly discovered examples of Class A FPMOs into a complete catalytic description of one enzymatic turnover.
Highlights
Common activating substitutents of aromatic molecules such as a hydroxyl or an amino group, facilitate catabolic degradation by enhancing nucleophilicity
The enzymes that carry out this early catabolic step are often flavoprotein monooxygenases (FPMOs)
Class A flavoprotein monooxygenases are the focus of this review
Summary
Common activating substitutents of aromatic molecules such as a hydroxyl or an amino group, facilitate catabolic degradation by enhancing nucleophilicity. The catabolism of such molecules provides access to considerable pool of energy for living organisms. All. FPMOs use the functionality of the reduced flavin isoalloxazine ring system to mediate the acquisition/reduction/activation of dioxygen. FPMOs use the functionality of the reduced flavin isoalloxazine ring system to mediate the acquisition/reduction/activation of dioxygen As such FPMOs most often require an external electron source such as reduced nicotinamide to first reduce the flavin by two electrons. It is not intended to be a chronology of the research of these enzymes and focuses instead on the more current ideas that have emerged regarding how enzyme structure directs the reaction forward
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