Structural, Mechanistic and Functional Studies on Oxgenases

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Proteins are polymers that are crucial to all aspects of life and which are biologically produced by polymerisation of monomeric amino acid precursors. In the early 20th century evidence was reported (by Henry Dakin) that proteins can react with atmospheric oxygen. Later it was found that penicillins are made from a tripeptide (three linked amino acids) by reaction with oxygen. Much more recently it was found that proteins that regulate how humans and other animals respond to limiting oxygen availability (hypoxia) are modified by direct reactions with oxygen, in a manner that decreases their activity. The reaction of these hypoxia inducible factors (HIFs) with oxygen signals for their degradation, so turning on the hypoxic response. The hypoxic response is of massive importance in human biology. If we go to high altitude we make more red blood cells to compensate for the reduced oxygen availability. Red blood cell production is stimulated by increases in the level of a hormone called erythropoietin (EPO), which in turn is increased by the HIFs. EPO is a really important medicine for the treatment of anaemia, but is an expensive protein to make and is not suitable for use by all anaemia sufferers. The hypoxic response is also important in cancer and the development of healthy animal physiology. If HIF degradation can be blocked by a drug EPO levels will increase and in turn red blood cell levels will increase, i.e. there is a new treatment for anaemia. PHD inhibitors have been developed but these are rather blunt instruments.Remarkably, the same family of oxygenases, i.e. enzymes using oxygen for catalysis, includes members that catalyse formation of penicillins from a tripeptide precursor (in effect a tiny protein) and enzymes that are the key regulators of the HIF mediated human hypoxic response - the PHDs. Previous BBSRC work has enabled the characterisation of these two types of oxygenases and shown related enzymes have roles in many other aspects of biology, including lipid metabolism and in the rapidly emerging field of epigenetics. Exactly how the oxygenase proteins interact with oxygen is not, however, well understood. In our new proposed BBSRC work we aim to elucidate the details of this process. In doing so we aim to inform on how dissolved gases interact with proteins in general, something of fundamental interest in biology, including from an evolutionary perspective, but on which there has been relatively little research. The results of our work will inform on how to make new antibiotics and make improved drugs for the treatment of anaemia and other hypoxic related diseases. The work will also enable the UK to remain at the forefront of basic science in research on oxygenases, a field of intense interest (as recognised by the 2019 Nobel prize for studies on the mechanisms of the human hypoxic response to which UK research contributed).