Investigating (di)terpenoid biosynthesis

研究（二）萜类生物合成

• 批准号: 10171598
• 负责人: REUBEN JOHN PETERS
• 金额: $ 53.72万
• 依托单位: IOWA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10171598
• 关键词: Anabolism; Antibiotics; Area; Biochemical Pathway; Biological; Carbon; Derivation procedure; Diterpenes; Engineering; Enzymes; Goals; Human; Hydrocarbons; Immune; Individual; Investigation; Labdanes; Lead; Libraries; Medicine; Metabolic Pathway; Metabolism; Mycobacterium tuberculosis; Natural Products; Pharmacologic Substance; Production; Skeleton; Structure; Terpenes; Terpenoid Biosynthesis Pathway; Vertebral column; Work; decalin; enzyme pathway; human pathogen; immunoregulation; isoprenoid; novel; pleuromutilin; scaffold; triptolide

Natural products have a proven record of providing a significant fraction, either directly or as lead compounds, of human medicines. Among natural products, the terpenoids (isoprenoids) stand out as being the largest class (>50,000 already known), with the 20-carbon diterpenoids targeted here forming a significant fraction of these (>12,000 known). The extensive diversification of diterpenoids indicates that the manifold hydrocarbon skeletons that can be formed from this C20 backbone, particularly the decalin core ring structure found in the labdane-related diterpenoids (>7,000 known), provide privileged scaffolds for derivation of biological activity. Indeed, a number of these labdane-related diterpenoids are used as pharmaceuticals (e.g., the antibiotic mutilins) or are being investigated for such use (e.g., the tanshinones, triptolide, andrographolide, etc.). In addition, we have contributed to the discovery that the human pathogen Mycobacterium tuberculosis utilizes labdane-related diterpenoid metabolism in construction of an immune-modulatory factor. Accordingly, we propose here to continue our productive studies of the biosynthetic enzymes required to produce bioactive diterpenoids. Specifically, we will build on our previous work in this area, which includes investigations of enzymatic structure-function that have provided novel biosynthetic access to an array of diterpenoids, as well as elucidation of strategically selected diterpenoid metabolic networks. This MIRA proposal covers our systematic studies in this area, advancing our long-term goal of engineering enzymes and metabolic pathways for the production of targeted libraries and specific individual terpenoid ‘natural’ products, which are being already using for investigation of pharmaceutical utility.

天然产品有一个被证明的记录，提供了一个显着的部分，无论是直接或作为铅 化合物，人类药物。在天然产物中，萜类化合物（类异戊二烯）突出为 是最大的一类（已知> 50，000），其中20个碳的二萜类化合物在这里形成了一个 其中很大一部分（已知> 12，000）。二萜类化合物的广泛多样性表明， 可以由该C20骨架形成的多种烃骨架，特别是十氢化萘 在劳丹相关的二萜类化合物（已知> 7，000种）中发现的核心环结构， 用于生物活性的衍生。事实上，许多这些劳丹相关的二萜类化合物被用作 药物（例如，抗生素木聚糖酶）或正在研究这种用途（例如，的 丹参酮、雷公藤内酯醇、穿心莲内酯醇等）。此外，我们还发现， 人类病原体结核分枝杆菌利用劳丹相关的二萜类代谢， 免疫调节因子的构建。因此，我们在此提议继续我们富有成效的工作， 研究生产生物活性二萜类所需的生物合成酶。具体来说，我们将建立 我们以前在这一领域的工作，其中包括研究酶的结构和功能， 提供了一系列二萜类化合物的新的生物合成途径，以及阐明了 选择的二萜类代谢网络。MIRA提案涵盖了我们在这一领域的系统研究， 推进我们的长期目标工程酶和代谢途径的生产 目标库和特定的单个萜类“天然”产品，这些产品已经用于 药物效用调查。