Pyruvate metabolism

The pyruvate metabolism pathway for Neospora caninum is same as the pathway for Toxoplasma gondii. The pathway of pyruvate metabolism in T. gondii and N. caninum has four separate components, of which the first three are present in Plasmodium falciparum.

 

  1. Pyruvate oxidation into acetyl-CoA – There are two isoforms of the enzyme pyruvate kinase in P. falciparum, T. gondii and N. caninum, one of which targets to apicoplast. In addition, the phosphoenolpyruvate/phosphate transporter is also localised to apicoplast membrane, which transports PEP to apicoplast. The pyruvate dehydrogenase complex is also present in apicoplast suggesting that oxidation of pyruvate to acetyl-CoA takes place in apicoplast [1].
  2. Anaplerotic (filling up) reactions – As the intermediates of citrate cycle are used up in biosynthetic reactions, oxaloacetate will be used up and need to be replenished. The enzymes PEP carboxykinase (Toxoplasma, Neospora and Plasmodium), PEP carboxylase (Plasmodium) and pyruvate carboxylase (Toxoplasma and Neospora) catalyse synthesis of oxaloacetate. Of these, the first two do not require energy source as they break energy rich phosphoenolpyruvate, whereas last enzyme require energy in the form of ATP. The enzymes aspartate transaminase and malate dehydrogenase present in Plasmodium, Neospora and Toxoplasma can convert oxaloacetate into 2-oxoglutarate and malate respectively which are intermediates of citrate cycle.
  3. Acetyl-CoA synthase and acetyltransferases - Acetyl-CoA synthase, acetate-CoA ligase, acetyl-CoA C-acetyltransferase, acetoacetyl-CoA reductase and peptide alpha-N-acetyltransferase are the other enzymes of this pathway present in both Coccidia and Plasmodium species.
  4. Alanine synthesis – The enzymes alanine dehydrogenase and alanine transaminase which catalyse alanine biosynthesis from pyruvate in a single step are present in T. gondii and N. caninum. It is a metabolic capability unique to these Coccidians and absent in other apicomplexans. The only difference between T. gondii and N. caninum in this branch of the pathway is the copy number variation of alanine dehydrogenase enzyme (2 in T. gondii and 3 in N. caninum).

 

Enzyme EC Number Gene id
Acetoacetyl-CoA reductase 1.1.1.36 NCLIV_026580
Malate dehydrogenase 1.1.1.37 NCLIV_011120
Pyruvate dehydrogenase E1 beta subunit (part of pyruvate dehydrogenase complex) 1.2.4.1 NCLIV_034990
Pyruvate dehydrogenase E1 alpha subunit (part of pyruvate dehydrogenase complex) 1.2.4.1 NCLIV_062940
Alanine dehydrogenase 1.4.1.1 NCLIV_021470
Alanine dehydrogenase 1.4.1.1 NCLIV_021480
Alanine dehydrogenase 1.4.1.1 NCLIV_058000
Dihydrolipoyl dehydrogenase (part of pyruvate dehydrogenase complex) 1.8.1.4 NCLIV_070190
Dihydrolipoamide S-acetyltransferase (part of pyruvate dehydrogenase complex) 2.3.1.12 NCLIV_044290
Peptide a-N-acetyltransferase 2.3.1.88 NCLIV_042130
Peptide a-N-acetyltransferase 2.3.1.88 NCLIV_060850
Acetyl-CoA C-acetyltransferase 2.3.1.9 NCLIV_069850
Aspartate transaminase 2.6.1.1 NCLIV_064760
Alanine transaminase 2.6.1.2 NCLIV_024040
Pyruvate kinase 2.7.1.40 NCLIV_009420
Pyruvate kinase 2.7.1.40 NCLIV_015200
PEP carboxykinase 4.1.1.49 NCLIV_041900
PEP carboxykinase 4.1.1.49 NCLIV_042160
Carbonic anhydrase 4.2.1.1 NCLIV_006180
Carbonic anhydrase 4.2.1.1 NCLIV_026960
Acetate-CoA ligase/Acetyl-CoA synthetase 6.2.1.1; 6.2.1.13 NCLIV_032540
Acetate-CoA ligase/Acetyl-CoA synthetase 6.2.1.1; 6.2.1.13 NCLIV_039400
Pyruvate carboxylase 6.4.1.1 NCLIV_028990
PEP/Pi tranlocator none NCLIV_026210
Acetyl-CoA transporter none NCLIV_060190

 

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Sources and fates of metabolites

 

Substrate Source pathways Product Fate pathways
Phosphoenolpyruvate Glycolysis Malate Host
Pyruvate Glycolysis 2-oxoglutarate Tricarboxylic acid (TCA) cycle, Glutamate metabolism
L-Glutamate Glutamate metabolism Aspartate Aspartate and asparagin metabolism
Acetyl-CoA Tricarboxylic acid (TCA) cycle, Fatty acid recycling and degradation, Leucine, isoleucine and valine metabolism Acetyl-CoA Fatty acid elongation in the cytosol, Fatty acid elongation in the ER, Fatty acid biosynthesis in the Apicoplast