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.
Highlights
The human pathogen Mycobacterium tuberculosis (Mtb) likely utilizes host fatty acids as a carbon source during infection
Evidence for a role of gluconeogenesis in Mtb virulence comes from studies of isocitrate lyase ICL, an enzyme that operates in the glyoxylate shunt
We demonstrate that GPM2, a broad-specificity phosphatase[26], has fructose bisphosphatase (FBPase) activity that maintains Mtb gluconeogenesis in the absence of GLPX
Summary
The human pathogen Mycobacterium tuberculosis (Mtb) likely utilizes host fatty acids as a carbon source during infection. Loss of ICL abolished growth of Mtb on fatty acids in vitro and led to early clearance of the pathogen from the lungs of infected mice[4]. These phenotypes were attributed to a requirement for gluconeogenesis, as disruption of the glyoxylate shunt blocks the flow of carbon from fatty acids into this pathway. This interpretation, does not account for the fact that ICL functions as a methylisocitrate lyase in the methylcitrate cycle[5]. PEPCK’s anaplerotic activity brings into question whether the in vivo survival defect of PEPCK-deficient Mtb is solely due to disrupted gluconeogenesis
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