Structural Biology of Polyether Antibiotic Biosynthesis

聚醚抗生素生物合成的结构生物学

• 批准号: 10261453
• 负责人: Chu-Young Kim
• 金额: $ 15.1万
• 依托单位: UNIVERSITY OF TEXAS EL PASO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10261453
• 关键词: Acyl Carrier Protein; Acyltransferase; Anabolism; Anti-Bacterial Agents; Antibiotics; Antifungal Agents; Bacteria; Biochemical; Biogenesis; Biological Models; Chemicals; Complex; Crystallization; Cyclic Ethers; Cyclization; Development; Docking; Engineering; Ensure; Enzymes; Epoxide hydrolase; Epoxy Compounds; Family; Flavins; Foundations; Future; Gene Cluster; Goals; Investigation; Laboratories; Mixed Function Oxygenases; Molecular; Molecular Conformation; Natural Products; Nature; Organism; Pathway interactions; Pharmaceutical Chemistry; Pharmaceutical Preparations; Polyenes; Production; Property; Reaction; Research; Scheme; Solid; Streptomyces; Structure; Subgroup; Techniques; Testing; Therapeutic; Time; Vertebral column; Work; Yeasts; anti-cancer; base; dimer; drug development; enzyme biosynthesis; novel; novel therapeutics; polyketide synthase; programs; protein protein interaction; seal; structural biology

The overarching goal of our research program is to elucidate how nature produces polyether natural products. Polyethers are a subgroup of polyketide natural products and, as a class, they possess a wide range of useful activities, including antibacterial, antifungal, and anticancer properties. However, polyether drug development is hampered by our inability to quickly and efficiently synthesize natural polyethers and their derivatives for medicinal chemistry and drug optimization studies. This is due to the unusually complex structure of natural polyethers. An attractive solution to this problem is to biosynthesize complex polyethers using engineered laboratory-friendly organisms such as bacteria or yeast. This approach is expected to make countless new polyethers accessible for drug research. In order to create a robust and reliable polyether bioproduction platform, we must first achieve a detailed and comprehensive understanding of how polyethers are produced in living organisms. More than 100 different polyether natural products have been discovered so far, and examination of known polyether biosynthetic gene clusters show that all polyethers are generated via a common three-stage biosynthetic scheme. Stage 1: construction of the polyketide backbone by modular polyketide synthases. Stage 2: stereoselective epoxidation of the polyene intermediate by a monooxygenase. Stage 3: formation of the hallmark cyclic ether groups by one or more epoxide hydrolases. The universal nature of this scheme ensures that investigation of any one particular polyether biosynthesis pathway and its associated enzymes will lead to a general understanding of how nature generates polyethers. In this project, we will study the biosynthetic enzymes from the lasalocid A biosynthesis pathway from Streptomyces lasaliensis. Lasalocid A biosynthesis pathway is an excellent model system for studying how nature produces polyethers because it consists of just nine enzymes, yet it possesses all the hallmark chemical transformations of polyether biosynthesis.

我们的研究计划的总体目标是阐明自然如何产生聚醚 天然产品。聚乙烯是聚酮化合物天然产物的亚组，作为一类 拥有广泛的有用活动，包括抗菌，抗真菌和抗癌药 特性。但是，多醚药物的开发受到我们无法快速和 有效合成天然聚乙烯及其用于药物化学和药物的衍生物 优化研究。这是由于天然聚乙烯的异常复杂的结构。一个 解决此问题的有吸引力的解决方案是使用工程的生物合成复杂的聚乙烯 实验室友好的生物，例如细菌或酵母菌。这种方法有望做出 无数的新聚乙烯可用于药物研究。为了创建强大而可靠的 聚醚生物生产平台，我们必须首先实现详细而全面的 了解在生物体中如何生产聚乙烯。超过100个不同 到目前为止，已经发现了多醚天然产物，并检查已知的聚醚 生物合成基因簇表明所有聚乙烯均通过共同的三阶段产生 生物合成方案。第1阶段：通过模块化聚酮化合物的聚酮基主链的构建 合酶。阶段2：通过单加氧酶对多烯中间体的立体选择性环氧化。 阶段3：由一个或多个环氧水解酶形成标志性环节基团。这 该方案的普遍性质可确保对任何一个特定的聚乙烯进行调查 生物合成途径及其相关酶将导致人们对 大自然会产生聚乙烯。在这个项目中，我们将研究来自 Lasalicid A链霉菌链霉菌的生物合成途径。 LASALICID A生物合成 途径是研究自然如何产生聚乙烯的绝佳模型系统，因为它 仅由九种酶组成，但它具有所有标志性化学转化 聚醚生物合成。