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Ischemic (oxygen debt) stroke is caused by occlusion of an artery to the brain and is by far the most common form of stroke (88% of all strokes). In the United States, stroke killed 162,272 people in 2002 and as such is the third most common cause of death. Approximately 700,000 people suffer a new or recurrent stroke each year. Stroke is the leading cause of serious, long-term disability; there are around 5.5 million stroke survivors the majority of which are in some way disabled.
A lack of oxygen in the brain causes an abnormally large release of glutamate that kills neurons by excessive stimulation. Glutamate acts by attaching to N-methyl-D-asparate (NMDA) receptors. Interestingly, a number of NMDA receptor antagonists and agonists are synthesized in the brain from tryptophan catabolism. In this pathway, kynurenine is consumed by three enzymes. Only one of these, that catalyzed by kynurenine 3-monooxygenase (KMO), is an irreversible reaction that dictates, entirely or in part, the concentration of four important signalling molecules. The inhibition of KMO, decreases the concentration of the primary NMDA agonist, quinolinate, it also decreases the concentration of two programmed cell death molecules, 3-hydroxykynurenine and xanthurenate. However, KMO inhibition also increases a primary NMDA antagonist, kynurenate that has the additional benefit of suppressing glutamate release.
The objective of our research is to characterize the KMO reaction coordinate in sufficient detail to allow the development of new inhibitors that will ultimately lead to new treatments for hypoxia in the brain. The research will use a range of methods including basic spectrophotometric investigation, crystallographic structural studies detailed rapid-mixing pre-steady state analysis, and human cell culture methods. KMO is a largely uncharacterized enzyme, and as such we intend to solve the structure of the enzyme in complex with substrates or known inhibitors. We intend also to define what about its catalytic mechanism is unique from the magnitude of isotope effects associated with the formation or decay of intermediates.
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