Structure and mechanism of a trans-acyltransferase polyketide synthase

聚酮化合物是人类已知的最重要的化合物之一，它们在自然界中扮演着许多重要的角色，如激素、毒素、香料、气味和色素。这些化合物也是许多用于治疗癌症、降低胆固醇、抑制免疫系统和抗感染的医学重要药物的基础。基于聚酮化合物的药物的销售额每年总计超过300亿英镑，并且全世界对鉴定新的聚酮化合物和制造现有聚酮化合物的新的和改进的版本有巨大的兴趣。聚酮化合物在微生物中由称为聚酮化合物脱氢酶的蛋白质簇产生，通常缩写为PKS。PKS的功能就像细胞内的微型工厂装配线。装配线内的每种不同蛋白质负责构建或修饰聚酮化合物产物的碳骨架的特定部分。不同微生物来源的PKS所合成的聚酮化合物在结构和活性上存在较大差异。尽管所有这些化合物都是由相同的初始化学构建模块产生的。理解这些差异是如何实现的依赖于对PKS如何工作的深入了解，本质上，装配线上的每种蛋白质都做什么，它们是如何做到的，以及它们如何相对于彼此排列？该研究项目将专注于一个新的PKS家族，该家族产生用于治疗一系列不同疾病的高度不寻常的产品。通过使用一种称为X射线晶体学的技术详细检查PKS组件的结构，我们将试图弄清楚PKS的每个不同部分是如何工作的，以及它们是如何组合在一起并相互作用的。这些实验不仅可以让我们破译这些系统如何制造它们的重要产品，而且还可以为我们提供一个蓝图，我们可以用它来构建新的PKS，从而制造新药。

Polyketides are among the most important compounds known to man. They perform many vital roles in nature acting as hormones, toxins, flavours, smells and pigments. These compounds are also the basis of numerous medically important drugs used to treat cancer, lower cholesterol, suppress the immune system and fight infection. Sales of polyketide based medicines total over £30 billion each year and there is enormous worldwide interest in identifying new polyketides and making new and improved versions of existing ones. Polyketides are made within microorganisms by clusters of proteins called polyketide synthases, usually shortened to PKSs. PKSs function like miniature factory assembly lines within cells. Each different protein within the assembly line is responsible for building or modifying a specific part of the carbon skeleton of the polyketide product. There are considerable differences in the structures and activities of different polyketides made by different PKSs from different microorganisms. This is despite the fact that all of these compounds are produced from the same initial chemical building blocks. Understanding how these differences are achieved relies on an in-depth knowledge of how PKSs work, essentially, what do each of the proteins in the assembly line do, how do they do it and how are they arranged relative to each other? This research project will focus on a new family of PKSs which generate highly unusual products used to treat a range of different diseases. By examining the structures of the components of the PKS in fine detail using a technique called X-ray crystallography, we will try to work out how each of different parts of the PKS works and how they fit together and interact with each other. These experiments will not only allow us to decipher how these systems make their important products, but will also provide us with a blue-print that we can use to construct new PKSs which make new medicines.