• Open Access

The 2-methylcitrate cycle is implicated in the detoxification of propionate in Toxoplasma gondii

Authors

  • Julien Limenitakis,

    1. Department of Microbiology and Molecular Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland
    Search for more papers by this author
    • Both authors contributed equally to this work.
  • Rebecca D. Oppenheim,

    1. Department of Microbiology and Molecular Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland
    Search for more papers by this author
    • Both authors contributed equally to this work.
  • Darren J. Creek,

    1. Wellcome Trust Center for Molecular Parasitology, University of Glasgow, Glasgow, UK
    2. Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, Australia
    Search for more papers by this author
  • Bernardo J. Foth,

    1. Department of Microbiology and Molecular Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland
    2. Wellcome Trust Sanger Institute, Hinxton, UK
    Search for more papers by this author
  • Michael P. Barrett,

    1. Wellcome Trust Center for Molecular Parasitology, University of Glasgow, Glasgow, UK
    Search for more papers by this author
  • Dominique Soldati-Favre

    Corresponding author
    • Department of Microbiology and Molecular Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland
    Search for more papers by this author

For correspondence. E-mail dominique.soldati-favre@unige.ch; Tel. (+41) 22 379 5672; Fax (+41) 22 379 5702.

Summary

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.

Ancillary