Structural Biology of Polyether Antibiotic Biosynthesis

我们研究计划的首要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亚组，作为一类，它们 具有广泛的有用活性，包括抗细菌、抗真菌和抗癌 特性.然而，聚醚药物的开发受到我们无法快速和 高效合成天然聚醚及其衍生物用于药物化学和药物 优化研究这是由于天然聚醚的结构异常复杂。一个 该问题的有吸引力的解决方案是使用工程化的生物合成复合聚醚， 实验室友好的有机体，如细菌或酵母。预计这一做法将使 无数新的聚醚可用于药物研究。为了创建一个强大而可靠的 聚醚生物生产平台，首先要实现详细全面的 了解聚醚是如何在生物体中产生的。100多种不同 迄今为止，已经发现了聚醚天然产物， 生物合成基因簇表明，所有聚醚都是通过一个共同的三个阶段产生的， 生物合成方案阶段1：通过模块化聚酮化合物构建聚酮化合物主链 - 是的阶段2：通过单加氧酶对多烯中间体进行立体选择性环氧化。 阶段3：通过一种或多种环氧化物水解酶形成标志性环醚基团。的 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的酶将导致对如何 大自然产生聚醚。在这个项目中，我们将研究来自 拉沙洛西A来自拉萨利链霉菌的生物合成途径。拉沙洛西A生物合成 pathway是研究自然界如何产生聚醚的极好模型系统，因为它 由九种酶组成，但它拥有所有标志性的化学转化， 聚醚生物合成

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.