Schofield Group

Chemistry Research Laboratory | Department of Chemistry

The 2-oxoglutarate (2OG) dependent oxygenases are a superfamily of non-haem iron dependent oxygenases, most of which use the Krebs cycle intermediate, 2-oxoglutarate (2OG), as a cosubstrate. We are interested in understanding these enzymes for their ability to catalyse synthetically difficult or ‘impossible’ reactions (e.g. the stereoselective hydroxylation of unactivated carbon-hydrogen bonds), for their diverse physiological roles, and for their links to disease.

 

The first members of the 2-oxoglutarate (2OG) dependent oxygenase family to be identified were prolyl and lysyl hydroxylases involved in collagen biosynthesis. Subsequently, 2OG oxygenases have been shown to catalyze oxidation reactions in most living organisms, ranging from bacteria and viruses to humans. In plants and microorganisms 2OG oxygenases catalyze many reactions employing small molecule substrates, notably involved in fatty acid metabolism and biosynthesis pathways leading to medicinally important antibiotics. Following the discovery of a role for the 2OG oxygenases in oxygen sensing, we, and others, have identified roles for 2OG oxygenases in protein synthesis at the transcriptional level (e.g. demethylation of histone and nucleic acids) and translational level (e.g. hydroxylation of ribosomes and translational machinery).
 

There are estimated to be 60-80 human 2OG oxygenases. One overall aim of our group is to define, or enable others to define functions for all human 2OG oxygenases at biochemical, cellular, and physiological level. We are particularly interested in members of the family that are linked to disease, or can be targeted for the treatment of disease. Techniques involved in this interdisciplinary research include proteomics, X-ray crystallography, biological mass spectrometry, molecular biology, kinetics and organic synthesis/medicinal chemistry.