Microbial Biotechnology, Faculty of Biology and Biotechnology, Ruhr-Universität Bochum, Universitätsstr. 150, 44780, Bochum, Germany.
Environmental Microbiology, Faculty of Chemistry and Physics, TU Bergakademie Freiberg, Leipziger Str. 29, 09599, Freiberg, Germany.
Appl Microbiol Biotechnol. 2020 Aug;104(15):6481-6499. doi: 10.1007/s00253-020-10705-w. Epub 2020 Jun 5.
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 .
天然存在的氨基酸或（二）胺衍生的氨基可以作为“穿梭物”在自然界中用于氧转移，以提供包含 N-O 官能团的中间体或产物，如 N-羟、嗪、异唑烷、硝基、硝酮、肟、C-、S-或 N-亚硝、和偶氮基单元。为此，黄素、血红素或金属辅因子酶激活分子氧，并将其转移以最初获得 N-羟化合物，其可以进一步官能化。在本综述中，我们重点介绍黄素依赖性 N-羟化酶，其在次生代谢产物（如铁载体或抗菌剂）的产生中起主要作用。高等生物（包括人类）的黄素蛋白单加氧酶可以与含氮次生代谢物相互作用，或者与解毒代谢有关，因此对于理解潜在的医学应用很重要。许多催化 N-羟化反应的酶具有特定的底物范围，而其他酶则较为宽松。随后向各种包含 N-O 或 N-N 的分子的转化也被描述。总体而言，黄素依赖性 N-羟化酶可以接受胺、二胺、氨基酸、氨基糖和氨基芳香化合物，从而提供多种包含 N-O 基序的化合物。强调了天然作用和合成应用。重点 • 强调了包含 N-O 和 N-N 的天然和（半）合成产物。 • 综述了基于黄素的 NMO 的机制、结构和系统发育。 • 提供了在天然产物形成和合成方法中的应用。
