Structure and mechanism of a trans-acyltransferase polyketide synthase

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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.