Glucose Phosphorylation Is Required for Mycobacterium tuberculosis Persistence in Mice

PLoS Pathogens

Kyu Y. Rhee¹  Carolina Trujillo²  Sabine Ehrt²  Joeli Marrero² 

[1] Department of Medicine, Weill Cornell Medical College, New York, New York, United States of America;Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York, United States of America

关键词: Mycobacterium tuberculosis;    Glucose metabolism;    Glucose;    Phosphorylation;    Trehalose;    Enzyme metabolism;    Drug metabolism;    Tuberculosis drug discovery;   

DOI  :  10.1371/journal.ppat.1003116

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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. 13C-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.

【 授权许可】

CC BY