Two enzymes with redundant fructose bisphosphatase activity sustain gluconeogenesis and virulence in Mycobacterium tuberculosis

Uday Ganapathy, Joeli Marrero, Susannah Calhoun, Hyungjin Eoh, Luiz Pedro Sorio D Carvalho, Kyu Rhee & Sabine Ehrt

Nature Communication 2015 Aug 6:7912

Speaker: Shu-Yun Wang (王舒韻)                                Time: 13:00~14:00, Nov, 18 2015

Commentator: Dr. Chang-Shi Chen(陳昌熙 老師)    Place: Room 601

Abstract:

        One-third of the world population is latently infected with Mycobacterium tuberculosis (Mtb) and this reservoir is expected to contribute towards an increasing incidence of tuberculosis (TB). Mtb is a resilient intracellular bacterium capable of infecting and surviving within host macrophages. It is likely to use fatty acids instead of glycolytic substrates as carbon source during infection. Thus, gluconeogenesis is critical to Mtb’s to cause disease. Fructose bisphosphatase (FBPase) catalyse is the rate-limiting step of gluconeogenesis, which converts fructose 1,6-bisphosphate (FBP) to fructose 6-phosphate. Unlike other steps in gluconeogenesis, the FBPase reaction is unidirectional and is specific to this pathway. Therefore, the Mtb mutant lacking FBPase activity will disrupt gluconeogenesis allowing assessing the specific role of gluconeogenesis in Mtb virulence. GlpX encodes the only annotated FBPase in the Mtb genome. The author generated a gplX deletion mutant (ΔglpX) and unexpectedly found that glpX is not essential for in vitro growth of Mtb on glycerol and fatty acids. They further demonstrated that GPM2 has FBPase activity that maintains gluconeogenesis in ΔglpX Mtb. Only the deletion of both GLPX and GPM2 FBPase disrupted gluconeogenesis. In conclusion, through interrupting gluconeogenesis, Mtb ΔglpXΔgpm2 is unable to establish infection. The authors proposed that this better understanding of how defective gluconeogenesis contributes to clearance of Mtb could identify alternative targets for new TB drugs.

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