07 November 2016
AJS McFadzean Distinguished Lecture
Maintenance of oxygen homeostasis is a fundamental physiology challenge and hypoxia is a component of many human diseases. The transcriptional response to hypoxia is mediated by hypoxia inducible factor (HIF), the oxygen sensitive signal being generated by a series of protein hydroxylases that catalyse prolyl and asparaginyl hydroxylation at specific residues in the regulatory HIF-alpha subunits. In the presence of oxygen prolyl hydroxylation directs HIF-alpha for destruction by the pVHL-ubiquitin-proteasome pathway, whilst asparaginyl hydroxylation blocks recruitment of co-activators. The HIF hydroxylases belong to two distinct groups of Fe(II) and 2-oxoglutarate dependent dioxygenase, which split dioxygen and couple oxidation (hydroxylation) of HIF-alpha to the oxidative decarboxylation of 2-oxoglutarate to succinate and carbon dioxide. This lecture will review recent advances in understanding of the HIF hydroxylase system, including its pan-genomic transcriptional organization and role in the integrated physiology of oxygen homeostasis, as well as its tractability as a therapeutic target.