title: Dual role of isocitrate lyase 1 in the glyoxylate and methylcitrate cycles in Mycobacterium tuberculosis.
abstract: 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 beta-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 effects. Although the genome of M. tuberculosis encodes orthologues of two of the three enzymes of the methylcitrate cycle, methylcitrate synthase and methylcitrate dehydratase, it does not appear to contain a distinct 2-methylisocitrate lyase (MCL). Detailed structural analysis of the MCL from Escherichia coli suggested that the differences in substrate specificity between MCLs and ICLs could be attributed to three conserved amino acid substitutions in the active site, suggesting an MCL signature. However, here we provide enzymatic evidence that shows that despite the absence of the MCL signature, ICL1 from M. tuberculosis can clearly function as a MCL. Furthermore, the crystal structure of ICL1 with pyruvate and succinate bound demonstrates that the active site can accommodate the additional methyl group without significant changes to the structure.
authors.affiliation: Department of Biochemistry and Biophysics, Texas A & M University, College Station, TX 77843, USA.
authors.forename: Ty A
authors.initials: TA
authors.lastname: Gould
authors.forename: Helmus
authors.initials: H
authors.lastname: van de Langemheen
authors.forename: Ernesto J
authors.initials: EJ
authors.lastname: Muñoz-Elías
authors.forename: John D
authors.initials: JD
authors.lastname: McKinney
authors.forename: James C
authors.initials: JC
authors.lastname: Sacchettini
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry* / Q000302:isolation & purification; D019755:Carbon-Carbon Lyases / Q000378:metabolism; D002950:Citrate (si)-Synthase / Q000378:metabolism; D002951:Citrates / Q000378:metabolism*; D003461:Crystallography; D005227:Fatty Acids / Q000378:metabolism; D006038:Glyoxylates / Q000378:metabolism*; D007522:Isocitrate Lyase / Q000737:chemistry* / Q000302:isolation & purification; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000201:enzymology* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D011487:Protein Conformation; D019289:Pyruvic Acid / Q000378:metabolism; D019802:Succinic Acid / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D002951:Citrates; D005227:Fatty Acids; D006038:Glyoxylates; D019289:Pyruvic Acid; D019802:Succinic Acid; D002950:Citrate (si)-Synthase; D019755:Carbon-Carbon Lyases; C402427:icl protein, Mycobacterium; C092884:methylcitrate synthase; D007522:Isocitrate Lyase; C417277:methylisocitrate lyase; C031150:glyoxylic acid