title: Two enzymes with redundant fructose bisphosphatase activity sustain gluconeogenesis and virulence in Mycobacterium tuberculosis.
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.
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, 413 East 69th Street, New York, New York 10021, USA.
authors.forename: Uday
authors.initials: U
authors.lastname: Ganapathy
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, 413 East 69th Street, New York, New York 10021, USA.
authors.forename: Joeli
authors.initials: J
authors.lastname: Marrero
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, 413 East 69th Street, New York, New York 10021, USA.
authors.forename: Susannah
authors.initials: S
authors.lastname: Calhoun
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, New York 10021, USA.
authors.forename: Hyungjin
authors.initials: H
authors.lastname: Eoh
authors.affiliation: Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, Mill Hill, London NW71AA, UK.
authors.forename: Luiz Pedro Sorio
authors.initials: LPS
authors.lastname: de Carvalho
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, New York 10021, USA.
authors.forename: Kyu
authors.initials: K
authors.lastname: Rhee
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, 413 East 69th Street, New York, New York 10021, USA.
authors.forename: Sabine
authors.initials: S
authors.lastname: Ehrt
mesh_terms: D006597:Fructose-Bisphosphatase / Q000378:metabolism*; D005943:Gluconeogenesis; D008094:Lithium; D009169:Mycobacterium tuberculosis / Q000201:enzymology* / Q000472:pathogenicity; D014774:Virulence
chemical_list: D008094:Lithium; D006597:Fructose-Bisphosphatase