两种具有冗余果糖双磷酸酶活性的酶维持结核分枝杆菌的糖异生和毒力。

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

作者信息

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

机构信息

Department of Microbiology and Immunology, Weill Cornell Medical College, 413 East 69th Street, New York, New York 10021, USA.

Department of Medicine, Weill Cornell Medical College, New York, New York 10021, USA.

出版信息

Nat Commun. 2015 Aug 10;6:7912. doi: 10.1038/ncomms8912.

The human pathogen Mycobacterium tuberculosis (Mtb) likely utilizes host fatty acids as a carbon source during infection. Gluconeogenesis is essential for the conversion of fatty acids into biomass. A rate-limiting step in gluconeogenesis is the conversion of fructose 1,6-bisphosphate to fructose 6-phosphate by a fructose bisphosphatase (FBPase). The Mtb genome contains only one annotated FBPase gene, glpX. Here we show that, unexpectedly, an Mtb mutant lacking GLPX grows on gluconeogenic carbon sources and has detectable FBPase activity. We demonstrate that the Mtb genome encodes an alternative FBPase (GPM2, Rv3214) that can maintain gluconeogenesis in the absence of GLPX. Consequently, deletion of both GLPX and GPM2 is required for disruption of gluconeogenesis and attenuation of Mtb in a mouse model of infection. Our work affirms a role for gluconeogenesis in Mtb virulence and reveals previously unidentified metabolic redundancy at the FBPase-catalysed reaction step of the pathway.

人类病原体结核分枝杆菌（Mtb）在感染过程中可能利用宿主脂肪酸作为碳源。糖异生对于将脂肪酸转化为生物量至关重要。糖异生中的一个限速步骤是果糖二磷酸酶（FBPase）将1,6-二磷酸果糖转化为6-磷酸果糖。Mtb基因组仅包含一个注释的FBPase基因，即glpX。在此我们意外地发现，缺乏GLPX的Mtb突变体能够在糖异生碳源上生长，并且具有可检测到的FBPase活性。我们证明Mtb基因组编码一种替代FBPase（GPM2，Rv3214），在缺乏GLPX的情况下它可以维持糖异生。因此，在感染的小鼠模型中，要破坏糖异生并减弱Mtb的毒力，需要同时缺失GLPX和GPM2。我们的工作证实了糖异生在Mtb毒力中的作用，并揭示了该途径中FBPase催化反应步骤中以前未被识别的代谢冗余。