Flavin-dependent N-hydroxylating enzymes: distribution and application

Abstract

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 NO 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 cofactorcontaining 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 NO 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 NO motif. Natural roles as well as synthetic applications are highlighted. Key points • NO 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.

Blocks in the pseudouridimycin pathway unlock hidden metabolites in the Streptomyces producer strain

“…A key step in the pathway appears to be the conversion of APU into Gln-APU by PumK, a conversion controlled by the regulator PumF. The detection of OH-Gln-APU suggests that N -hydroxylation by PumE precedes addition of GAA by PumM, consistent with the well-known facilitated hydroxylation of amines with respect to amides 33 . In the absence of PumE, PumM uses Gln-APU as substrate, leading to deoxyPUM as a shunt metabolite.…”

Metabolomic investigation of the pseudouridimycin producer, a prolific streptomycete

“…The detection of OH-Gln-APU is consistent with the possibility that N -hydroxylation by PumE precedes GAA addition by PumM, consistent with the well-known facilitated hydroxylation of amines with respect to amides. 32 In the absence of PumE, PumM can use Gln-APU as substrate, leading to deoxyPUM as a shunt metabolite. While in the absence of PumM, Gln-APU preferentially accumulates, suggesting that either conversion of Gln-APU into its hydroxyderivative is inefficient or expression of pumE is altered in such background.…”

Characterization of a broadly specific cadaverine N-hydroxylase involved in desferrioxamine B biosynthesis in Streptomyces sviceus

“…These NMOs play an essential role in committing diamines to the biosynthesis of hydroxamate siderophores, which are used to sequester iron for microorganisms, including several human pathogens. Furthermore, they are used in the industrial fermentation of pharmaceuticals, such as desferrioxamine B, and are currently being explored as biocatalysts, as they accept complex substrates and introduce the unique N-O functionality in a single step, which can be further derivatized [ 45 ]. However, they are not as well-studied as the L-lysine and L-ornithine NMOs, particularly those involved in the biosynthesis of nocobactin in N .…”