The biosynthesis and enzymology of complex rubromycin and tropone marine bacterial natural products

复合红霉素和托品酮海洋细菌天然产物的生物合成和酶学

• 批准号: 439507043
• 负责人: Professor Dr. Robin Teufel
• 金额: --
• 依托单位: Institut für Mikrobiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2020
• 资助国家: 德国
• 起止时间: 2019-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/439507043?language=en
• 关键词: biosynthesis; enzymology; complex; rubromycin; tropone

Marine natural products remained a largely untapped and underexplored source of pharmaceutically interesting compounds for a long time. Meanwhile, numerous bioactive marine natural products have been characterized, many of which derive from bacteria. Often, these molecules feature highly intricate structures that impede or completely thwart chemical synthesis, while their biosynthesis depends on unusual enzyme reactions. My research project focusses on the detailed characterization of the enzymology underlying the biosynthesis of ecologically and pharmaceutically interesting natural products that, e.g., serve as defensive tools for marine invertebrates (corals, tunicates, oysters, or sponges), as exemplified by tropone-based natural products such as tropodithietic acid or rosebacticides. These compounds are produced, e.g., by predominant marine bacteria such as Roseobacter or coral-associated Pseudovibrio sp., where they serve as potent coral protectants, algaecides, or bacterial signaling molecules. In the past, we elucidated the bacterial phenylacetic acid catabolic pathway and identified the postulated precursor for tropone natural products. We now aim to acquire all enzymes required for the biosynthesis of thee metabolites and characterize them in detail to enable the in vitro enzymatic synthesis of these natural products and gain insight into the underlying biochemistry. As a second pillar of the project, the biosynthesis of the rubromycin family of aromatic polyketides will be investigated that are produced by Actinobacteria, which are commonly isolated from marine tunicates. Until recently, little details were known about the biosynthesis of rubromycins, in particular of the spiroketal pharmacophore that is exceptional among aromatic polyketides and essential for their potent bioactivities. We successfully reconstituted the complete enzymatic spiroketal pharamacophore formation in vitro that granted insight into novel enzyme reactions and led to the discovery of various previously unrecognized intermediates. We now seek to solve the structures of these enzymes and conduct detailed mechanistic studies to further our understanding of these complex biosynthetic steps. Moreover, final pathway steps that modify the spiroketal will be investigated. Taken together, both project parts aim at elucidating the enzymology underlying the biosyntheses of ecologically and pharmaceutically relevant marine natural products. This knowledge may be useful, e.g., for the establishment of in vivo and in vitro production platforms and bioengineering of bioactive compounds, while also furthering our fundamental understanding of how structural complexity is generated in nature.

很长一段时间以来，海洋天然产品仍然是一个很大程度上未开发和未充分开发的药学上有趣的化合物来源。与此同时，许多具有生物活性的海洋天然产物已被表征，其中许多来源于细菌。通常，这些分子具有高度复杂的结构，阻碍或完全阻碍化学合成，而它们的生物合成依赖于不寻常的酶反应。我的研究项目集中于生物学的详细特征，这些生物学是生态学和药理学上有趣的天然产物的生物合成的基础，例如，作为海洋无脊椎动物（珊瑚，被囊动物，牡蛎或海绵）的防御工具，例如trotro酮基天然产物，如tropo二甲酸或玫瑰杀菌剂。这些化合物是由主要的海洋细菌如玫瑰杆菌或与珊瑚相关的假弧菌产生的，在那里它们可以作为有效的珊瑚保护剂、杀藻剂或细菌信号分子。在过去，我们阐明了细菌苯乙酸的分解代谢途径，并确定了托酮天然产物的假定前体。我们现在的目标是获得三种代谢物生物合成所需的所有酶，并详细表征它们，以使这些天然产物的体外酶合成成为可能，并深入了解潜在的生物化学。作为该项目的第二个支柱，将研究由放线菌产生的红霉素家族芳香聚酮的生物合成，放线菌通常从海洋被囊动物中分离出来。直到最近，人们对红霉素的生物合成知之甚少，特别是在芳香聚酮中特殊的螺旋酮药效团，它对其有效的生物活性至关重要。我们成功地在体外重建了完整的酶促螺旋酮药团形成，从而深入了解了新的酶反应，并发现了各种以前未被识别的中间体。我们现在寻求解决这些酶的结构，并进行详细的机制研究，以进一步了解这些复杂的生物合成步骤。此外，最后的途径步骤，修改螺旋将被研究。总而言之，这两个项目部分旨在阐明生物学基础的生物合成的生态和药学相关的海洋天然产品。这些知识可能是有用的，例如，对于建立体内和体外生产平台和生物活性化合物的生物工程，同时也进一步加深我们对结构复杂性如何在自然界中产生的基本理解。