Discovery of Stealthin Derivatives and Implication of the Amidotransferase FlsN3 in the Biosynthesis of Nitrogen-Containing Fluostatins.

• 影响指数: 6.085
• 发表时间: Mar 2019 4
• 来源期刊: Mar Drugs
• DOI: 10.3390/md17030150
• PMID: 30836614
• 文章类型: Journal Article
• 中科院分区: Q1
• 方向: 医学
• 作者列表: Huang C,Yang C,Fang Z,Zhang L,Zhang W,Zhu Y,Zhang C

关键词: Micromonospora; N–N bond; angucyclines; biosynthesis; gene inactivation; marine; raceme

Mesh: Aquatic Organisms / metabolism; Bacterial Proteins / genetics metabolism; Biosynthetic Pathways; Computational Biology; Crystallography, X-Ray; Fluorenes / chemistry isolation & purification metabolism; Heterocyclic Compounds, 4 or More Rings / chemistry; Magnetic Resonance Spectroscopy; Micromonospora / metabolism; Molecular Structure; Nitrogen / chemistry; Streptomyces; Transaminases / genetics metabolism

Abstract

Diazobenzofluorene-containing atypical angucyclines exhibit promising biological activities. Here we report the inactivation of an amidotransferase-encoding gene flsN3 in Micromonospora rosaria SCSIO N160, a producer of fluostatins. Bioinformatics analysis indicated that FlsN3 was involved in the diazo formation. Chemical investigation of the flsN3-inactivation mutant resulted in the isolation of a variety of angucycline aromatic polyketides, including four racemic aminobenzo[b]fluorenes stealthins D⁻G (9⁻12) harboring a stealthin C-like core skeleton with an acetone or butanone-like side chain. Their structures were elucidated on the basis of nuclear magnetic resonance (NMR) spectroscopic data and X-ray diffraction analysis. A plausible mechanism for the formation of stealthins D⁻G (9⁻12) was proposed. These results suggested a functional role of FlsN3 in the formation/modification of N⁻N bond-containing fluostatins.