title: The 2-methylcitrate cycle is implicated in the detoxification of propionate in Toxoplasma gondii.
abstract: Toxoplasma gondii belongs to the coccidian subgroup of the Apicomplexa phylum. The Coccidia are obligate intracellular pathogens that establish infection in their mammalian host via the enteric route. These parasites lack a mitochondrial pyruvate dehydrogenase complex but have preserved the degradation of branched-chain amino acids (BCAA) as a possible pathway to generate acetyl-CoA. Importantly, degradation of leucine, isoleucine and valine could lead to concomitant accumulation of propionyl-CoA, a toxic metabolite that inhibits cell growth. Like fungi and bacteria, the Coccidia possess the complete set of enzymes necessary to metabolize and detoxify propionate by oxidation to pyruvate via the 2-methylcitrate cycle (2-MCC). Phylogenetic analysis provides evidence that the 2-MCC was acquired via horizontal gene transfer. In T. gondii tachyzoites, this pathway is split between the cytosol and the mitochondrion. Although the rate-limiting enzyme 2-methylisocitrate lyase is dispensable for parasite survival, its substrates accumulate in parasites deficient in the enzyme and its absence confers increased sensitivity to propionic acid. BCAA is also dispensable in tachyzoites, leaving unresolved the source of mitochondrial acetyl-CoA.
authors.affiliation: Department of Microbiology and Molecular Medicine, Faculty of Medicine, University of Geneva, CMU 1 Rue Michel Servet, 1211 Geneva, Switzerland.
authors.forename: Julien
authors.initials: J
authors.lastname: Limenitakis
authors.forename: Rebecca D
authors.initials: RD
authors.lastname: Oppenheim
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Creek
authors.forename: Bernardo J
authors.initials: BJ
authors.lastname: Foth
authors.forename: Michael P
authors.initials: MP
authors.lastname: Barrett
authors.forename: Dominique
authors.initials: D
authors.lastname: Soldati-Favre
mesh_terms: D000214:Acyl Coenzyme A / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D019755:Carbon-Carbon Lyases / Q000235:genetics / Q000378:metabolism; D002951:Citrates / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D010802:Phylogeny; D011422:Propionates / Q000378:metabolism* / Q000633:toxicity; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism; D014122:Toxoplasma / Q000145:classification / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D014123:Toxoplasmosis / Q000469:parasitology*
chemical_list: D000214:Acyl Coenzyme A; D002951:Citrates; D011422:Propionates; D015800:Protozoan Proteins; C009061:propionyl-coenzyme A; C031605:2-methylcitric acid; D019755:Carbon-Carbon Lyases; C417277:methylisocitrate lyase