title: GarA is an essential regulator of metabolism in Mycobacterium tuberculosis.
abstract: Alpha-ketoglutarate is a key metabolic intermediate at the crossroads of carbon and nitrogen metabolism, whose fate is tightly regulated. In mycobacteria the protein GarA regulates the tricarboxylic acid cycle and glutamate synthesis by direct binding and regulation of three enzymes that use α-ketoglutarate. GarA, in turn, is thought to be regulated via phosphorylation by protein kinase G and other kinases. We have investigated the requirement for GarA for metabolic regulation during growth in vitro and in macrophages. GarA was found to be essential to Mycobacterium tuberculosis, but dispensable in non-pathogenic Mycobacterium smegmatis. Disruption of garA caused a distinctive, nutrient-dependent phenotype, fitting with its proposed role in regulating glutamate metabolism. The data underline the importance of the TCA cycle and the balance with glutamate synthesis in M. tuberculosis and reveal vulnerability to disruption of these pathways.
authors: Department of Molecular Medicine, University of Padua, Via Gabelli 63, Padova, Italy.
authors: Marcello
authors: M
authors: Ventura
authors: Barbara
authors: B
authors: Rieck
authors: Francesca
authors: F
authors: Boldrin
authors: Giulia
authors: G
authors: Degiacomi
authors: Marco
authors: M
authors: Bellinzoni
authors: Nathalie
authors: N
authors: Barilone
authors: Faisal
authors: F
authors: Alzaidi
authors: Pedro M
authors: PM
authors: Alzari
authors: Riccardo
authors: R
authors: Manganelli
authors: Helen M
authors: HM
authors: O'Hare
mesh_terms: D001426:Bacterial Proteins / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D002952:Citric Acid Cycle; D015964:Gene Expression Regulation, Bacterial; D005798:Genes, Bacterial; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D007656:Ketoglutaric Acids / Q000378:metabolism*; D008264:Macrophages / Q000382:microbiology; D016297:Mutagenesis, Site-Directed; D020102:Mycobacterium smegmatis / Q000235:genetics* / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D010766:Phosphorylation; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D007656:Ketoglutaric Acids; D011994:Recombinant Proteins; D018698:Glutamic Acid