2-Methylcitrate cycle

Many organisms can provide a carbon source in the form of acetyl-CoA for fatty acid biosynthesis via the tricarboxylic acid (citrate) shuttle (TCA cycle). Mitochondrial pyruvate dehydrogenase is absent and  the complex is localised to the apicoplast in apicomplexans such as Plasmodium, Toxoplasma and Neospora. This suggests that the TCA cycle depends on other oxidation/degradation pathways  rather than glycolysis-derived pyruvate for acetyl-CoA.  The enzymes for the complete Leucine, isoleucine and valine degradation pathway are present in the Toxoplasma gondii genome. The degradation of isoleucine and valine leads to the production of propionyl-CoA, which is toxic and inhibits cell growth [1]. The methyl-citrate cycle, a pathway present in bacteria and fungi, can metabolise propionyl-CoA into pyruvate that can be used as a source of carbon [2]. The genes for the enzymes catalysing this 2-methylcitrate cycle are present in T. gondii [3]. It is suggested to be a mitochondrial pathway as it shares enzymes with the citrate cycle. Except aconitate hydratase, a common enzyme of both the 2-methylcitrate cycle and the citrate cycle, other enzymes are not predicted to be targeted to the mitochondria by the bioinformatics tools available (see below).

 

Enzyme EC Number Gene id Protein localisation Localisation data source
2-methylcitrate synthase 2.3.3.5 TGME49_263130 Cytosol; Cytoskeleton GO annotation; Previous publication
2-methylisocitrate lyase 4.1.3.30 TGME49_293810 Cytosol Previous publication
aconitate hydratase 4.2.1.3 TGME49_226730 Apicoplast; Mitochondrion Apiloc; Previous publication
2-methylcitrate dehydratase 4.2.1.79 TGME49_213680 Cytosol Previous publication
Pyruvate carboxylase 6.4.1.1 TGME49_284190 Apicoplast Previous publication

 

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Sources and fates of metabolites

 

Substrate Source pathways Product Fate pathways
Propanoyl-CoA Leucine, isoleucine and valine metabolism Succinate Tricarboxylic acid (TCA) cycle