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Structure and mechanism of a trans-acyltransferase polyketide synthase

转酰基转移酶聚酮合酶的结构和机制

基本信息

批准号：
BB/I006478/1
负责人：
Paul Race
金额：
$ 42.76万
依托单位：
University of Bristol
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2011
资助国家：
英国
起止时间：
2011 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FI006478%2F1
关键词：
Structure mechanism trans acyltransferase polyketide

项目摘要

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.

聚酮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，充当荷尔蒙、毒素、香料、气味和色素。这些化合物也是许多医学上重要的药物的基础，这些药物用于治疗癌症、降低胆固醇、抑制免疫系统和抗感染。聚酮类药物的销售总额每年超过300亿GB，全世界对识别新的聚酮类化合物和制造现有聚酮类药物的新版本和改进版本有着极大的兴趣。聚酮在微生物中是由称为聚酮合成酶的蛋白质簇形成的，通常简称为PKS。PKSS的功能就像细胞内的微型工厂装配线。装配线中的每个不同的蛋白质负责构建或修饰聚酮产品的碳骨架的特定部分。不同微生物来源的PKS所形成的不同多酮的结构和活性有很大的差异。尽管所有这些化合物都是从相同的初始化学成分中产生的，但这仍然是事实。要理解这些差异是如何实现的，取决于对PKS如何工作的深入了解，本质上，装配线上的每个蛋白质都做什么，它们是如何做到的，它们是如何相对于彼此排列的？这项研究项目将集中在一种新的PKS家族上，这种家族产生非常不寻常的产品，用于治疗一系列不同的疾病。通过使用一种名为X射线结晶学的技术详细研究PKS组件的结构，我们将试图找出PKS的每个不同部分是如何工作的，以及它们是如何组装在一起并相互作用的。这些实验不仅让我们能够破译这些系统是如何制造他们的重要产品的，而且还将为我们提供一个蓝图，我们可以用它来构建制造新药的新的PKS。