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Regulation of glutamate metabolism by protein kinases in mycobacteria

By Helen M. O'Hare, Rosario Durán, Carlos Cerveñansky, Marco Bellinzoni, Anne Marie Wehenkel, Otto Pritsch, Gonzalo Obal, Jens Baumgartner, Jérome Vialaret, Kai Johnsson and Pedro M. Alzari

Abstract

This paper was published as Molecular Microbiology, 2008, 70 (6), pp. 1408-1423. The definitive version is available at www3.interscience.wiley.com. Doi: 10.1111/j.1365-2958.2008.06489.xMetadata only entryProtein kinase G of Mycobacterium tuberculosis has been implicated in virulence and in regulation of glutamate metabolism. Here we show that this kinase undergoes a pattern of autophosphorylation that is distinct from that of other M. tuberculosis protein kinases characterized to date and we identify GarA as a substrate for phosphorylation by PknG. Autophosphorylation of PknG has little effect on kinase activity but promotes binding to GarA, an interaction that is also detected in living mycobacteria. PknG phosphorylates GarA at threonine 21, adjacent to the residue phosphorylated by PknB (T22), and these two phosphorylation events are mutually exclusive. Like the homologue OdhI from Corynebacterium glutamicum, the unphosphorylated form of GarA is shown to inhibit α-ketoglutarate decarboxylase in the TCA cycle. Additionally GarA is found to bind and modulate the activity of a large NAD+-specific glutamate dehydrogenase with an unusually low affinity for glutamate. Previous reports of a defect in glutamate metabolism caused by pknG deletion may thus be explained by the effect of unphosphorylated GarA on these two enzyme activities, which may also contribute to the attenuation of virulence

Publisher: Wiley-Blackwell
Year: 2008
DOI identifier: 10.1111/j.1365-2958.2008.06489.x
OAI identifier: oai:lra.le.ac.uk:2381/4749
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