The genome of Mycobacterium tuberculosis contains 11 serine threonine protein kinases. Amongst these PknA, PknB and PknG are essential for bacterial survival and/or virulence, and are considered potential drug targets. This proposal aims to elucidate the functions of PknB and PknG, with particular focus on the regulation of primary metabolism. PknB is reported to be involved in the control of cell-shape, whereas PknG might function as a regulator of metabolism or as a virulence protein secreted into the macrophage. Based on a study of the related microbe Corynebacterium glutamicum, preliminary work has been done to investigate a possible role for PknG (and possibly PknB) in regulation of the citric acid cycle. In corynebacteria PknG controls the phosphorylation status of a small regulatory protein GarA, which directly inhibits the ODH complex. First experiments with mycobacteria suggest that this regulatory mechanism is probably conserved and may also be employed to regulate nitrogen metabolism in these organisms. An experimental strategy is proposed to investigate the regulation of kinase activity and determine the effects of kinase activity on carbon and nitrogen metabolism.
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