Glucose phosphorylation is required for Mycobacterium tuberculosis persistence in mice.
Glucose phosphorylation is required for Mycobacterium tuberculosis persistence in mice.
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DOI：
10.1371/journal.ppat.1003116
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发表时间：
2013-01
期刊：
影响因子：
6.7
通讯作者：
Ehrt S
中科院分区：
文献类型：
--
作者：
Marrero J;Trujillo C;Rhee KY;Ehrt S
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. The development of new drugs targeting Mycobacterium tuberculosis (Mtb) will benefit from a better understanding of the mechanisms by which this pathogen establishes and maintains chronic infections. Mtb has to adapt its metabolic needs to the nutritional environment in the host. We investigated the role of glucose phosphorylation and discovered that Mtb expresses two functional glucokinases. Using 13C-tracing experiments we demonstrated that both enzymes are competent to incorporate glucose into central carbon metabolism. In agreement with the view that Mtb metabolizes fatty acids to grow in vivo, both enzymes were dispensable for Mtb replication in mouse lungs and spleens. Surprisingly, however, the glucokinase double mutant was attenuated during the chronic phase of mouse infections. These studies suggest that Mtb metabolizes glucose in vivo and that its survival in chronically infected mice depends on glucose phosphorylation.
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DOI：
10.1086/656524
发表时间：
2010-11-01
期刊：
The Journal of infectious diseases
影响因子：
--
作者：
Klinkenberg LG;Lee JH;Bishai WR;Karakousis PC
通讯作者：
Karakousis PC
影响因子：
4.9
作者：
Bruning, John B.;Murillo, Ana C.;Sacchettini, James C.
通讯作者：
Sacchettini, James C.
影响因子：
82.9
作者：
Muñoz-Elías, EJ;McKinney, JD
通讯作者：
McKinney, JD
DOI：
10.1073/pnas.1631248100
发表时间：
2003-08-19
影响因子：
11.1
作者：
Dahl, JL;Kraus, CN;Barry, CE
通讯作者：
Barry, CE
影响因子：
15.9
作者：
Niederweis M;Danilchanka O;Huff J;Hoffmann C;Engelhardt H
通讯作者：
Engelhardt H