Defining the physiology and therapeutic potential of oxygenases as signalling enzymes. (360G-Wellcome-106244_Z_14_Z)

Our joint work has led to the elucidation of hypoxia signalling pathways that employ 2-oxoglutarate (2OG) oxygenase-catalysed protein hydroxylation to sense changing cellular O2 levels. Together with other recent assignments of biological oxidations catalysed by 2OG oxygenases (including many conducted in Oxford), these findings raise important questions as to the wider potential of the 2OG oxygenases as signalling vectors, and whether these basic discoveries can be harnessed for therapeutic ben efit. Our overall goal is to enable new therapies through basic science studies on mechanisms of human oxygen(ase) regulated biochemistry and physiology. We aim to focus on questions with the greatest potential to inform basic understanding and/or medical application and will work at different levels ranging from translational approaches that test therapeutic strategies, to basic physiological and biochemical studies. Our research questions are: What physiologically relevant oxidations are catalysed by these enzymes? What is the role of these reactions in signalling hypoxic, metabolic and related stresses? What are their roles in disease and what is their therapeutic potential?