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。聚醚是聚酮类天然产物的一个子族，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 属性。然而，聚醚药物的开发受到我们无法快速和 药物化学和药物用天然聚醚及其衍生物的高效合成 优化研究。这是由于天然聚醚的结构异常复杂。一个 解决这一问题的有吸引力的方案是利用工程合成复杂的聚醚 实验室友好的生物，如细菌或酵母菌。这种方法预计将使 无数新的聚醚可用于药物研究。为了创造一个稳健可靠的 聚醚生物生产平台，首先要做到精细化全面 了解聚醚是如何在生物体内产生的。100多种不同的 到目前为止，已发现聚醚天然产物，并对已知聚醚进行了检验 生物合成基因簇表明，所有的聚醚都是通过共同的三个阶段产生的。 生物合成方案。阶段1：用模块化聚酮构建聚酮骨架 合成酶。阶段2：用单加氧酶立体选择性地环氧化多烯中间体。 阶段3：一个或多个环氧化物水解酶形成标志性环醚基团。这个 这一计划的普遍性确保了对任何一种特定聚醚的调查 生物合成途径及其相关的酶将导致对如何 大自然会产生聚醚。在这个项目中，我们将研究从生物合成酶 拉萨洛菌素A的生物合成途径。拉沙洛西德A的生物合成 路径是研究自然界如何产生聚醚的一个很好的模型系统，因为它 只由九种酶组成，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.