Structural Biology of Polyether Antibiotic Biosynthesis

聚醚抗生素生物合成的结构生物学

• 批准号: 10036330
• 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/10036330
• 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.

我们研究计划的总体目标是阐明自然界如何产生聚醚 天然产品。聚醚是聚酮化合物天然产物的一个子类，作为一类，它们 具有广泛的有用活性，包括抗菌、抗真菌和抗癌 特性。然而，聚醚药物的开发因我们无法快速、有效地开发而受到阻碍。 高效合成用于药物化学和药物的天然聚醚及其衍生物 优化研究。这是由于天然聚醚的结构异常复杂。一个 解决这个问题的一个有吸引力的解决方案是使用工程化生物合成复杂的聚醚 实验室友好的生物体，例如细菌或酵母。这种方法预计将使 无数新的聚醚可用于药物研究。为了创建一个坚固可靠的 聚醚生物生产平台，首先要实现详细全面 了解生物体中聚醚是如何产生的。超过100种不同 迄今为止已发现聚醚天然产物，并对已知聚醚进行检验 生物合成基因簇表明所有聚醚都是通过共同的三阶段生成的 生物合成方案。第一阶段：通过模块化聚酮化合物构建聚酮化合物主链 合酶。第2阶段：通过单加氧酶对多烯中间体进行立体选择性环氧化。 第 3 阶段：通过一种或多种环氧化物水解酶形成标志性环醚基团。这 该方案的普遍性确保了对任何一种特定聚醚的研究 生物合成途径及其相关酶将导致对如何进行的一般理解 自然界产生聚醚。在这个项目中，我们将研究来自植物的生物合成酶。 拉沙里菌素 (lasalocid) 来自拉萨链霉菌 (Streptomyces lasaliensis) 的生物合成途径。拉沙里菌素A生物合成 途径是研究自然如何产生聚醚的优秀模型系统，因为它 仅由九种酶组成，但它具有所有标志性的化学转化 聚醚生物合成。