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Mycobacterium tuberculosis  requires the enzyme isocitrate lyase (ICL) for growth and virulence  in vivo . The demonstration that  M. tuberculosis  also requires ICL for survival during nutrient starvation and has a role during steady state growth in a glycerol limited chemostat indicates a function for this enzyme which extends beyond fat metabolism. As isocitrate lyase is a potential drug target elucidating the role of this enzyme is of importance; however, the role of isocitrate lyase has never been investigated at the level of  in vivo  fluxes. Here we show that deletion of one of the two  icl  genes impairs the replication of  Mycobacterium bovis  BCG at slow growth rate in a carbon limited chemostat. In order to further understand the role of isocitrate lyase in the central metabolism of mycobacteria the effect of growth rate on the  in vivo  fluxes was studied for the first time using  13 C-metabolic flux analysis (MFA). Tracer experiments were performed with steady state chemostat cultures of BCG or  M. tuberculosis  supplied with  13 C labeled glycerol or sodium bicarbonate. Through measurements of the  13 C isotopomer labeling patterns in protein-derived amino acids and enzymatic activity assays we have identified the activity of a novel pathway for pyruvate dissimilation. We named this the GAS pathway because it utilizes the Glyoxylate shunt and Anapleurotic reactions for oxidation of pyruvate, and Succinyl CoA synthetase for the generation of succinyl CoA combined with a very low flux through the succinate – oxaloacetate segment of the tricarboxylic acid cycle. We confirm that  M. tuberculosis  can fix carbon from CO 2  into biomass. As the human host is abundant in CO 2  this finding requires further investigation  in vivo  as CO 2  fixation may provide a point of vulnerability that could be targeted with novel drugs. This study also provides a platform for further studies into the metabolism of  M. tuberculosis  using  13 C-MFA.

plos pathogens

13C Metabolic Flux Analysis Identifies an Unusual Route for Pyruvate Dissimilation in Mycobacteria which Requires Isocitrate Lyase and Carbon Dioxide Fixation