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.

长期以来，海洋天然产品一直是药物有趣化合物的未被开发和未置换的源。同时，已经表征了许多生物活性海洋天然产品，其中许多源自细菌。通常，这些分子具有高度复杂的结构，这些结构会阻碍或完全阻止化学合成，而它们的生物合成依赖于异常的酶反应。我的研究项目的重点是生态和药品有趣的自然产品的生物合成的详细表征，例如，这些天然产物是海洋无脊椎动物（珊瑚，束肌，牡蛎或sp）的防御性工具，例如基于Tropone的天然产物，例如Tropone天然产物，例如Tropone Products，例如Tropododieticic accticicices。这些化合物是由主要的海洋细菌（例如玫瑰杆菌或珊瑚相关的伪卵杆菌）产生的，它们是有效的珊瑚保护剂，藻类或细菌信号分子。过去，我们阐明了细菌苯乙酸分解代谢途径，并确定了tropone天然产物的假定前体。现在，我们的目标是获取您代谢物的生物合成所需的所有酶，并详细表征它们，以实现这些天然产物的体外酶合成，并深入了解基本的生物化学。作为该项目的第二个支柱，将研究芳香族聚酮化合物的生物合成，该家族将由静脉细菌产生，通常是从海洋束缚中分离出来的。直到最近，关于rubromycins的生物合成的了解很少，尤其是在芳族聚酮化合物中非常例外的螺旋粒药片，对于它们的有效生物活性至关重要。我们成功地重新建立了体外酶促的卷骨干菌落形成，该杂化剂形成赋予了对新型酶反应的见解，并导致发现了各种以前未知的中间体。现在，我们寻求解决这些酶的结构并进行详细的机械研究，以进一步了解这些复杂的生物合成步骤。此外，将研究修改螺旋体的最终途径步骤。综上所述，这两个项目部分旨在阐明生态和药物相关的海洋天然产品的生物合成基础的酶学。这些知识可能很有用，例如，对于建立体内和体外生产平台以及生物活性化合物的生物工程，同时也进一步增进了我们对自然界结构复杂性如何产生的基本了解。