Functional assignments on human oxygenases

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Regulating oxygen delivery to cells is a problem for all aerobic organisms ranging from bacteria to humans. In mammals, the lungs, heart and blood are all devoted to this task, and human diseases (such as strokes, heart attacks and anaemia) often involve damage to organs by low oxygen levels (hypoxia). Basic science work supported by the BBSRC has provided insights into how cells 'sense' and respond to hypoxia. The work has helped to identify a set of 'oxygenases' (a type of enzyme that catalyses the incorporation of atmospheric oxygen into their substrates) that catalyse the addition of oxygen atoms to a protein called hypoxia inducible factor (HIF), so called because its level is raised under low oxygen concentrations. HIF is important as it occurs in a very wide range of organisms including insects, worms and humans; it enables the expression of a range of genes that work to help the organism overcome the challenge of hypoxia. In humans these genes enable a response to hypoxia and include those involved in blood vessel and red blood cell formation. Addition of oxygen to HIF stops its ability to enable the expression of the genes involved in the hypoxic response. When there is sufficient oxygen the oxygenases can catalyse its addition to HIF, but when oxygen levels fall HIF is no longer modified and it is free to enable expression of the genes involved in the hypoxic response. We hope that the results of this work will result in new treatments for diseases involving the cardiovascular system. By inhibiting the HIF oxygenases with small molecule drugs, it should be possible to improve the body's natural defence against damage from low oxygen concentrations. However to do this safely without causing side effects will require more knowledge of other human oxygenases, that have been revealed by analysis of the human genome. The work on the HIF system has raised questions as to the extent of the role of oxygenases in controlling the expression of genes in other pathways and indeed biology as a whole. This proposal seeks to go some way towards addressing these questions by studying human oxygenases, some of which are known to be biomedicinally important from work at the physiological level but for which there is little or no data in terms of their actual substrates and roles at a biochemical level. There are technical problems in working with human cells compared to, for example, those from microorganisms. However, we have chosen to work with human enzymes, in part, because the worldwide efforts in genome sequencing and other large scale projects studying the proteins present in human cells have provided a resource we can utilise to help assign biochemical roles for the oxygenases, and, in part, because we hope that the work will be useful in the development of new therapies based on a better understanding of human metabolism.