Acetyl-CoA-mediated activation of Mycobacterium tuberculosis isocitrate lyase 2

Isocitrate lyase is important for lipid utilisation by Mycobacterium tuberculosis but its ICL2 isoform is poorly understood. Here we report that binding of the lipid metabolites acetyl-CoA or propionyl-CoA to ICL2 induces a striking structural rearrangement, substantially increasing isocitrate lyase and methylisocitrate lyase activities. Thus, ICL2 plays a pivotal role regulating carbon flux between the tricarboxylic acid (TCA) cycle, glyoxylate shunt and methylcitrate cycle at high lipid concentrations, a mechanism essential for bacterial growth and virulence. Isocitrate lyase (ICL) isoforms 1 and 2 are enzymes in the glyoxylate and methylcitrate cycles that enable Mycobacterium tuberculosis (Mtb) to use lipids as a carbon source. Here the authors present the ligand-free Mtb ICL2 and acetyl-CoA bound ICL2 crystal structures, which reveal a structural reorganisation upon acetyl-CoA binding that leads to an activation of its isocitrate lyase and methylcitrate lyase activities.