title: Glucose phosphorylation is required for Mycobacterium tuberculosis persistence in mice.
abstract: Mycobacterium tuberculosis (Mtb) is thought to preferentially rely on fatty acid metabolism to both establish and maintain chronic infections. Its metabolic network, however, allows efficient co-catabolism of multiple carbon substrates. To gain insight into the importance of carbohydrate substrates for Mtb pathogenesis we evaluated the role of glucose phosphorylation, the first reaction in glycolysis. We discovered that Mtb expresses two functional glucokinases. Mtb required the polyphosphate glucokinase PPGK for normal growth on glucose, while its second glucokinase GLKA was dispensable. (13)C-based metabolomic profiling revealed that both enzymes are capable of incorporating glucose into Mtb's central carbon metabolism, with PPGK serving as dominant glucokinase in wild type (wt) Mtb. When both glucokinase genes, ppgK and glkA, were deleted from its genome, Mtb was unable to use external glucose as substrate for growth or metabolism. Characterization of the glucokinase mutants in mouse infections demonstrated that glucose phosphorylation is dispensable for establishing infection in mice. Surprisingly, however, the glucokinase double mutant failed to persist normally in lungs, which suggests that Mtb has access to glucose in vivo and relies on glucose phosphorylation to survive during chronic mouse infections.
authors: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York, USA.
authors: Joeli
authors: J
authors: Marrero
authors: Carolina
authors: C
authors: Trujillo
authors: Kyu Y
authors: KY
authors: Rhee
authors: Sabine
authors: S
authors: Ehrt
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D055786:Gene Knockout Techniques; D005941:Glucokinase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D055432:Metabolomics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000201:enzymology / Q000472:pathogenicity*; D010766:Phosphorylation; D010770:Phosphotransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity; D014376:Tuberculosis / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology
chemical_list: D001426:Bacterial Proteins; D002250:Carbon Radioisotopes; D010770:Phosphotransferases; C096446:GlkA protein, Bacteria; D005941:Glucokinase; C024812:polyphosphate-glucose phosphotransferase; D005947:Glucose