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

Author

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  • Uday Ganapathy

    (Weill Cornell Medical College, 413 East 69th Street, New York, New York 10021, USA)

  • Joeli Marrero

    (Weill Cornell Medical College, 413 East 69th Street, New York, New York 10021, USA)

  • Susannah Calhoun

    (Weill Cornell Medical College, 413 East 69th Street, New York, New York 10021, USA)

  • Hyungjin Eoh

    (Weill Cornell Medical College)

  • Luiz Pedro Sorio de Carvalho

    (Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, Mill Hill, London NW71AA, UK)

  • Kyu Rhee

    (Weill Cornell Medical College)

  • Sabine Ehrt

    (Weill Cornell Medical College, 413 East 69th Street, New York, New York 10021, USA)

Abstract

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.

Suggested Citation

  • Uday Ganapathy & Joeli Marrero & Susannah Calhoun & Hyungjin Eoh & Luiz Pedro Sorio de Carvalho & Kyu Rhee & Sabine Ehrt, 2015. "Two enzymes with redundant fructose bisphosphatase activity sustain gluconeogenesis and virulence in Mycobacterium tuberculosis," Nature Communications, Nature, vol. 6(1), pages 1-12, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8912
    DOI: 10.1038/ncomms8912
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