Abstract
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.
Highlights
Isocitrate lyase is important for lipid utilisation by Mycobacterium tuberculosis but its ICL2 isoform is poorly understood
The regulation of carbon flux between the tricarboxylic acid (TCA) cycle and glyoxylate shunt is critical for Mycobacterium tuberculosis (Mtb), especially given its ability to utilise multiple carbon sources simultaneously[1]
We have shown that activation of the isocitrate lyase activity of ICL2 occurs upon acetyl-CoA and propionyl-CoA binding, uncovering the unique role this isoform plays in the allosteric regulation of the glyoxylate shunt at high lipid concentrations
Summary
Isocitrate lyase is important for lipid utilisation by Mycobacterium tuberculosis but its ICL2 isoform is poorly understood. 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. Isocitrate lyase (ICL) isoforms 1 and 2 (Supplementary Fig. 1) are key enzymes in this process, through their roles in the glyoxylate and methylcitrate cycles (Supplementary Fig. 2)[5,6]. Our results provide strong evidence that ICL2 may act as a gate-keeping enzyme, allosterically regulating the glyoxylate shunt and the methylcitrate cycle, an essential mechanism during chronic infection when Mtb uses lipids as the primary carbon source
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