Scheme: University Research Fellowship
Organisation: University of Bristol
Dates: Oct 2009-Sep 2014
Summary: Polyketides are some of 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, with sales of polyketide based medicines totaling over £30 billion each year. 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 growing polyketide. There are considerable differences in the structures and activities of different polyketides, made by different PKSs, from different micro-organisms. 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? One of the best ways to understand how something works is to look at it! Unfortunately as proteins are very small, they can’t be seen using a conventional light microscope. One of the best ways of looking at the structures of proteins is to use a technique called X-ray crystallography. Individual protein molecules can be made to bind to each forming crystals which when exposed to X-rays, produce a distinctive pattern that can be seen and recorded. By analysing these patterns it is possible to build a 3D model of the structure of the crystallised protein. My research involves using this technique to examine proteins that make-up different PKSs. By rationally altering the PKS structures it may be possible to make novel PKSs, producing designer polyketides with unique properties which may then be used as the basis for new drugs.