Flavin-dependent N -hydroxylating enzymes: distribution and application

Amino groups derived from naturally abundant amino acids or (di)amines can be used as “shuttles” in nature for oxygen transfer to provide intermediates or products comprising N-O functional groups such as N -hydroxy, oxazine, isoxazolidine, nitro, nitrone, oxime, C -, S -, or N -nitroso, and azoxy units. To this end, molecular oxygen is activated by flavin, heme, or metal cofactor-containing enzymes and transferred to initially obtain N -hydroxy compounds, which can be further functionalized. In this review, we focus on flavin-dependent N -hydroxylating enzymes, which play a major role in the production of secondary metabolites, such as siderophores or antimicrobial agents. Flavoprotein monooxygenases of higher organisms (among others, in humans) can interact with nitrogen-bearing secondary metabolites or are relevant with respect to detoxification metabolism and are thus of importance to understand potential medical applications. Many enzymes that catalyze N -hydroxylation reactions have specific substrate scopes and others are rather relaxed. The subsequent conversion towards various N-O or N-N comprising molecules is also described. Overall, flavin-dependent N -hydroxylating enzymes can accept amines, diamines, amino acids, amino sugars, and amino aromatic compounds and thus provide access to versatile families of compounds containing the N-O motif. Natural roles as well as synthetic applications are highlighted. Key points • N-O and N-N comprising natural and ( semi ) synthetic products are highlighted . • Flavin-based NMOs with respect to mechanism , structure , and phylogeny are reviewed . • Applications in natural product formation and synthetic approaches are provided . Graphical abstract .