High-throughput structural biology of metabolic enzymes and its impact on human diseases

The Structural Genomics Consortium (SGC) is a public-private partnership that aims to determine the three-dimensional structures of human proteins of medical relevance and place them into the public domain without restriction. To date, the Oxford Metabolic Enzyme Group at SGC has deposited the structures of more than 140 human metabolic enzymes from diverse protein families such as oxidoreductases, hydrolases, oxygenases and fatty acid transferases. A subset of our target proteins are involved in the inherited disorders of carbohydrate, fatty acid, amino acid and vitamin metabolism. This article will provide an overview of the structural data gathered from our high-throughput efforts and the lessons learnt in the structure-function relationship of these enzymes, small molecule development and the molecular basis of disease mutations.