Dual role of isocitrate lyase 1 in the glyoxylate and methylcitrate cycles in Mycobacterium tuberculosis

  title={Dual role of isocitrate lyase 1 in the glyoxylate and methylcitrate cycles in Mycobacterium tuberculosis},
  author={Ty A. Gould and Helmus van de Langemheen and Ernesto J. Mu{\~n}oz-El{\'i}as and John D. Mckinney and James C. Sacchettini},
  journal={Molecular Microbiology},
The role of isocitrate lyase (ICL) in the glyoxylate cycle and its necessity for persistence and virulence of Mycobacterium tuberculosis has been well described. Recent reports have alluded to an additional role for this enzyme in M. tuberculosis metabolism, specifically for growth on propionate. A product of β‐oxidation of odd‐chain fatty acids is propionyl‐CoA. Clearance of propionyl‐CoA and the by‐products of its metabolism via the methylcitrate cycle is vital due to their potentially toxic… 
Role of the methylcitrate cycle in propionate metabolism and detoxification in Mycobacterium smegmatis.
Deletion of the M. smegmatis prpDBC locus is shown to reduce but not eliminate MCL activity, suggesting that the marked attenuation of ICL1/ICL2-deficient M. tuberculosis in mice could be due to the accumulation of toxic propionyl-CoA metabolites, rather than inability to utilize fatty acids per se.
Acetyl-CoA-mediated activation of Mycobacterium tuberculosis isocitrate lyase 2
itrate lyase 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.
Major roles of isocitrate lyase and malate synthase in bacterial and fungal pathogenesis.
The glyoxylate cycle is an anaplerotic pathway of the tricarboxylic acid (TCA) cycle that allows growth on C(2) compounds by bypassing the CO(2)-generating steps of the TCA cycle. The unique enzymes
Methylcitrate cycle defines the bactericidal essentiality of isocitrate lyase for survival of Mycobacterium tuberculosis on fatty acids
It is reported that Mtb’s ICLs are essential for survival on both acetate and propionate because of its methylisocitrate lyase (MCL) activity, and a previously unrecognized link between Propionate metabolism and membrane bioenergetics is revealed.
Glyoxylate detoxification is an essential function of malate synthase required for carbon assimilation in Mycobacterium tuberculosis
It is demonstrated that Mtb MS enables growth and survival on fatty acids through its ability to simultaneously detoxify a metabolic byproduct arising from the initial assimilation of acetyl coenzyme A, glyoxylate, while assimilating a second molecule ofacetyl-CoA.
Modulation of Central Carbon Metabolism by Acetylation of Isocitrate Lyase in Mycobacterium tuberculosis
It is found that lysine acetylation plays an important role in the modulation of central carbon metabolism in M. tb cultures and another regulatory mechanism of ICL1 is uncovered.
Regulation of the icl1 Gene Encoding the Major Isocitrate Lyase in Mycobacterium smegmatis
The regulation mechanism underlying induction of icl1 expression in M. smegmatis when the glyoxylate shunt is required was revealed and it was suggested that succinyl-CoA serves as a coinducer molecule for RamB.
Potential Inhibitors for Isocitrate Lyase of Mycobacterium tuberculosis and Non-M. tuberculosis: A Summary
There are many approaches to discovering potential inhibitor for MTB ICL and the updated list of them is reviewed and each of the approaches is capable of overcoming different challenges of inhibitor discovery.
A Novel Role of the PrpR as a Transcription Factor Involved in the Regulation of Methylcitrate Pathway in Mycobacterium tuberculosis
It is shown that an M. tuberculosis prpR-deletion strain exhibits impaired growth in vitro on propionate as the sole carbon source, and the findings suggest that it plays a key role in regulating expression of enzymes involved in both glyoxylate and methylcitrate pathways.
Mycobacterium smegmatis GlnR Regulates the Glyoxylate Cycle and the Methylcitrate Cycle on Fatty Acid Metabolism by Repressing icl Transcription
The findings reveal the GlnR-mediated repression of icl on fatty acid metabolism, which might be a general strategy of nutrient sensing and environmental adaptation employed by mycobacteria.


Role of the methylcitrate cycle in Mycobacterium tuberculosis metabolism, intracellular growth, and virulence
Growth of bacteria and fungi on fatty acid substrates requires the catabolic β‐oxidation cycle and the anaplerotic glyoxylate cycle. Propionyl‐CoA generated by β‐oxidation of odd‐chain fatty acids is
Mycobacterium tuberculosis isocitrate lyases 1 and 2 are jointly required for in vivo growth and virulence
It is shown that prokaryotic and eukaryotic-like isoforms of the glyoxylate cycle enzyme isocitrate lyase (ICL) are jointly required for fatty acid catabolism and virulence in Mycobacterium tuberculosis.
Methylcitrate synthase from Aspergillus nidulans: implications for propionate as an antifungal agent
Propionate not only impaired hyphal growth of A. nidulans but also synthesis of the green polyketide‐derived pigment of the conidia, whereas in the mutant pigmentation was abolished with 20 mM propionate.
Residues C123 and D58 of the 2-Methylisocitrate Lyase (PrpB) Enzyme of Salmonella enterica Are Essential for Catalysis
ABSTRACT The prpB gene of Salmonella enterica serovar Typhimurium LT2 encodes a protein with 2-methylisocitrate (2-MIC) lyase activity, which cleaves 2-MIC into pyruvate and succinate during the
In vitro conversion of propionate to pyruvate by Salmonella enterica enzymes: 2-methylcitrate dehydratase (PrpD) and aconitase Enzymes catalyze the conversion of 2-methylcitrate to 2-methylisocitrate.
The phenotype of this double mutant indicates that the aconitase enzymes are required for the 2-methylcitric acid cycle during propionate catabolism, and shows that the prpD gene of thePrpBCDE operon of this bacterium encodes a protein with 2- methylcitrate dehydratase enzyme activity.
Structure of isocitrate lyase, a persistence factor of Mycobacterium tuberculosis
The structure of a C191S mutant of the enzyme with the inhibitor 3-nitropropionate provides further insight into the reaction mechanism and its potential as a drug target against persistent infections.
Crystal structure of 2-methylisocitrate lyase (PrpB) from Escherichia coli and modelling of its ligand bound active centre.
2-Methylisocitrate lyases from the bacterium Escherichia coli and the filamentous fungus Aspergillus nidulans: characterization and comparison of both enzymes.
In Escherichia coli and Aspergillus nidulans, propionate is oxidized to pyruvate via the methylcitrate cycle, the last step of which is catalysed by 2-methylisocitrate lyase, a native homotetrameric structure as identified by size-exclusion chromatography.
The structure and domain organization of Escherichia coli isocitrate lyase.
Comparison of the structure of the prokaryotic isocitrate lyase with that from the eukaryote Aspergillus nidulans reveals a different domain structure following the deletion of approximately 100 residues from the larger eUKaryotic enzyme.