Isocitrate Lyase Dynamics in Mycobacterial Metabolism

Isocitrate lyase (ICL) occupies a pivotal position in the metabolic network of pathogenic mycobacteria, enabling the utilisation of host-derived lipids during infection. By catalysing the cleavage of isocitrate into glyoxylate and succinate, ICL directs carbon flux away from the tricarboxylic acid (TCA) cycle into the glyoxylate shunt, thereby supporting gluconeogenesis and biomass synthesis under nutrient-limited conditions. Mycobacterium tuberculosis expresses two isoforms, ICL1 and ICL2, which show distinct regulatory properties and substrate preferences. ICL activity is modulated by post-translational modifications, allosteric effectors and protein–protein interactions, ensuring a dynamic balance between energy generation and anaplerotic replenishment. This flexibility underpins both acute growth on fatty acids and long-term persistence in host tissues, making ICL a validated target for chemotherapeutic intervention. Advances in structural biology, enzymology and systems-level analysis have begun to unravel the conformational landscapes and regulatory circuits that govern ICL function, revealing novel opportunities for selective inhibition and metabolic reprogramming of the pathogen.

Research from Nature Portfolio

Structural studies of the ICL2 isoform have revealed that binding of acyl-CoA derivatives such as acetyl-CoA or propionyl-CoA induces a pronounced rearrangement in the active-site architecture, simultaneously enhancing both isocitrate lyase and methylisocitrate lyase activities. This ligand-mediated activation establishes a feedback loop that tunes carbon partitioning between the glyoxylate shunt, methylcitrate cycle and the oxidative arm of the TCA cycle under high-lipid conditions, thereby sustaining virulence and growth on host lipids.

Investigations into the bifurcation of carbon flux have uncovered a rheostat-like mechanism in mycobacteria whereby glyoxylate produced by ICL allosterically activates isocitrate dehydrogenase (ICDH). This metabolite-mediated cross-activation maintains a stable division of isocitrate between the glyoxylate shunt and the TCA cycle, contrasting with the phosphorylation-based control observed in other bacteria. The discovery highlights the centrality of ICL in global flux regulation and identifies an intrinsic chemical sensor that could be exploited for therapeutic disruption of metabolic homeostasis.

Mutagenesis and molecular dynamics analyses have further demonstrated that distal residues outside the catalytic core can govern ICL stability and dynamics. A single point mutation at a surface-exposed phenylalanine residue markedly increased conformational flexibility in regions that close over the active site, leading to loss of enzymatic activity. This finding emphasises the potential of targeting allosteric hotspots rather than the conserved catalytic motif for selective inhibitor design.

Isocitrate Lyase Dynamics in Mycobacterial Metabolism publication trend

The graph below shows the total number of articles in isocitrate lyase dynamics in mycobacterial metabolism across all publications each year (not limited to Nature Index journals).

Technical terms

Isocitrate lyase (ICL): Enzyme that cleaves isocitrate into glyoxylate and succinate, enabling the glyoxylate shunt.

Glyoxylate shunt: Metabolic bypass of the TCA cycle that conserves carbon skeletons for gluconeogenesis during growth on lipids.

Methylcitrate cycle: Pathway that processes propionyl-CoA into pyruvate and succinate, important for odd-chain fatty acid catabolism.

Allosteric regulation: Modulation of enzyme activity through effector binding at sites distinct from the catalytic centre, altering conformation.

Carbon flux bifurcation: Division of a metabolic intermediate between two competing pathways, dictating energy production versus biosynthesis.

References

1. Acetyl-CoA-mediated activation of Mycobacterium tuberculosis isocitrate lyase 2. Nature Communications (2019).
2. A rheostat mechanism governs the bifurcation of carbon flux in mycobacteria. Nature Communications (2016).
3. Distant Phe345 mutation compromises the stability and activity of Mycobacterium tuberculosis isocitrate lyase by modulating its structural flexibility. Scientific Reports (2017).
4. Heterogeneous multimeric structure of isocitrate lyase in complex with succinate and itaconate provides novel insights into its inhibitory mechanism. PLOS ONE (2021).