Welcome to the Schofield Group Website


With Dr Emily Flashman (Dorothy Hodgkin Research Fellow) and Dr Christoph Loenarz (William R Miller Junior Research Fellow)

Introduction


The research of our group is driven by a desire to apply chemical principles and techniques to understanding biology. Most research projects in our group aim to combine interesting chemistry with important biomedicinal problems. Current projects involve investigations into how human cells respond to variations in oxygen supply, how complex antibiotics are made by biosynthesis in a few steps, how small molecules regulate transcription in humans, and on the chemical basis of epigenetics.

A long-standing focus of our research has been investigations on metallo-enzymes that catalyse reactions that are presently impossible for synthetic chemistry - such as the stereoselective oxidation of unactivated hydrocarbons. We are also interested in proteases and the variety of unusual enzymes involved in antibiotic biosynthesis with the carbapenems and clavam families of β-lactams being of special current interest.

A variety of techniques are used in the group, including synthetic chemistry, enzyme purification and characterisation, cloning/mutagenesis and biophysical techniques including X-ray crystallography, NMR (in collaboration with Dr Tim Claridge), and mass spectrometry (in collaboration with Dr James McCullagh).

We are keen to apply the knowledge gained in our basic research activities to medicine. A particular focus of our recent research has been the oxygen dependent regulation of the transcription factor hypoxia inducible factor (HIF) (in collaboration with Peter Ratcliffe and Chris Pugh). HIF is a master regulator of the transcriptional response to limiting oxygen concentrations in metazoan cells and controls the production of proteins such as erythropoietin (EPO) and vascular endothelial growth factor (VEGF) that work to supply cells with oxygen. The levels and activity of the α-subunit of HIF are regulated by its post-translational hydroxylation and the oxygen dependent HIF hydroxylases effectively act as oxygen sensors. We are interested in understanding the chemical and structural basis by which the HIF hydroxylases enable the hypoxic response. We aim to inspire the development of new treatments that employ modifications of HIF hydroxylase activity, including by their inhibition with small molecules.

The HIF hydroxylases belong to the ubiquitous family of ferrous iron and 2-oxoglutarate (2OG) dependent oxygenases. One overall aim of our group is to define, or enable others to define functions for all the human '2OG oxygenases' at biochemical, cellular, and physiological level. As part of this work we aim to obtain crystal structures and identify small-molecule inhibitors for human 2OG oxygenases, with a major current focus being histone/chromatin modifying enzymes (in collaboration with the Structural Genomics Consortium).

Our laboratories are located in the Chemistry Research Laboratory, in the Science Area of Oxford University.