Biosynthesis of merochlorins - A novel class of highly active halogenated polyketide antibiotics from marine Streptomyces sp.

氯氰菊酯的生物合成 - 来自海洋链霉菌的一类新型高活性卤化聚酮化合物抗生素。

• 批准号: 215534120
• 负责人: Professor Dr. Robin Teufel
• 金额: --
• 依托单位: Center for Marine Biotechnology and Biomedicine
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2011
• 资助国家: 德国
• 起止时间: 2010-12-31 至 2012-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/215534120?language=en
• 关键词: Biosynthesis; merochlorins; novel; class; highly

Marine microbes have recently emerged as an important source of chemically distinct antimicrobial agents with potential for medical applications in the treatment of infectious diseases or cancer. A plenitude of such compounds is synthesized by use of aromatic polyketide frameworks undergoing dedicated oxidative tailoring reactions, which strongly contribute to the compounds potent biological activities. Recently, some marine Streptomyces sp. were shown to produce a unique class of highly active, chlorinated polyketide antibiotics (merochlorins) that may be derived from prenylated and halogenated tetrahydroxynaphthalene precursors. Vanadium-dependent chloroperoxidases presumably catalyze the crucial cyclization and ring-expansion steps. This study aims at investigating the biosynthesis of the novel merochlorin antibiotics. The main focus of the project lies on the exploration of the biochemical steps leading to the modified tetrahydroxynaphthalene precursors, along with the examination of the proposed unprecedented chloroperoxidase-catalyzed macrocyclization and ring-formation/expansion reactions. Systematic gene inactivation, in vitro studies of heterologous proteins and their catalytic features, site-directed mutagenesis, and X-ray crystallography will be applied to functionally assign and characterize involved proteins and to expose the underlying reaction mechanisms, with the ultimate goal to establish biosynthetic pipelines for biological evaluation in antibiotic screens.

海洋微生物最近已成为化学上独特的抗菌剂的重要来源，具有在治疗传染病或癌症方面的医疗应用潜力。大量这类化合物是利用芳香族聚酮骨架经过专门的氧化剪裁反应合成的，这对化合物具有强大的生物活性有很大的贡献。近年来，一些海洋链霉菌属(Streptomyces sp.)被证明能产生一类独特的高活性氯化聚酮抗生素(美罗氯素)，这种抗生素可能来自异丙苯化和卤化的四羟基萘前体。依赖于钒的氯过氧化物酶可能催化关键的环化和扩环步骤。本研究旨在研究新型美罗氯抗生素的生物合成。该项目的主要重点是探索导致改性四氢萘前体的生化步骤，以及审查拟议的史无前例的氯过氧化物酶催化的大环化和成环/扩环反应。系统的基因失活、异源蛋白质及其催化特性的体外研究、定点突变和X射线结晶学将被用于对所涉及的蛋白质进行功能分配和表征，并揭示潜在的反应机制，最终目标是建立用于抗生素筛选的生物合成管道。