Pyruvate metabolism

The Piroplasma pathway of Pyruvate metabolism differs from the pathway of Plasmodium falciparum and Toxoplasma gondii in many aspects. The main difference between Piroplasma and Toxoplasma is the absence of the pyruvate dehydrogenase complex. The pathway of pyruvate metabolism in Apicomplexa has five separate components.

 

  1. Pyruvate oxidation into acetyl-CoA – In Plasmodium and Toxoplasma, pyruvate oxidation is catalysed by the pyruvate dehydrogenase complex of apicoplast. This oxidation is catalysed by the pyruvate:NADP(+) oxidoreductase in Cryptosporidia. The genes coding for both the enzymes are absent in Theileria and Babesia suggesting the absence of this capability.
  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 (both Toxoplasma and Plasmodium), PEP carboxylase (Plasmodium and Cryptosporidia) and pyruvate carboxylase (Toxoplasma) 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. PEP carboxykinase and PEP carboxylase are present in the genome of Babesia bovis, whereas PEP carboxylase is missing in the genomes of Theileria parva and Theileria annulata. The study by Kiama et al demonstrated the presence of activities of PEP carboxykinase and pyruvate carboxylase in T. parva schizont. They also observed 11-fold higher activity of pyruvate carboxylase than PEP carboxykinase [1]. The gene for pyruvate carboxylase is missing in the gene models of all three Piroplasma species. The oxaloacetate synthesised can be converted to malate with the action of malate dehydrogenase. Malate dehydrogenase is present in Plasmodium, Toxoplasma, Neospora, Cryptosporidium, Theileria and Babesia species.
  3. Acetyl-CoA synthase and acetyltransferases - Acetyl-CoA synthase, acetate-CoA ligase, acetoacetyl-CoA reductase and peptide alpha-N-acetyltransferase are the other enzymes of this pathway present in apicomplexan species. The enzyme acetyl-CoA C-acetyltransferase is present in Babesia bovis, but missing in the gene models of Theileria species.
  4. Fermentation reactions – The genes coding for the enzymes pyruvate decarboxylase, bifunctional aldehyde/alcohol dehydrogenase and alcohol dehydrogenase are present in Cryptosporidia genomes and absent in other apicomplexan genomes including those of Piroplasma species.
  5. Alanine synthesis – The enzymes alanine dehydrogenase and alanine transaminase which catalyse alanine biosynthesis from pyruvate are present in Toxoplasma gondii and Neospora caninum. This metabolic capability is absent in Plasmodium and Cryptosporidium species. Kiama et al demonstrated relatively high activity of alanine transaminase in T. parva schizont [1]. The presence of the activity of an enzyme transaminating pyruvate to alanine was also observed in Babesia rodhaini [2]. However, the gene for alanine transaminase is missing in the gene models of Piroplasma species and not added to the pathway here.

 

Enzyme EC Number Gene id
Acetoacetyl-CoA reductase 1.1.1.36 TP04_0605
Acetoacetyl-CoA reductase 1.1.1.36 TP04_0606
Peptide alpha-N-acetyltransferase 2.3.1.88 TP04_0161
Peptide alpha-N-acetyltransferase 2.3.1.88 TP04_0624
Acetyl-CoA C-acetyltransferase 2.3.1.9

Missing in annotation

Aspartate transaminase 2.6.1.1 TP02_0046
Pyruvate kinase 2.7.1.40 TP02_0134
Phosphoenolpyruvate carboxylase 4.1.1.31 Missing in annotation
PEP carboxykinase 4.1.1.49 TP01_0495
Carbonic anhydrase 4.2.1.1 TP02_0412
Acetate-CoA ligase/Acetyl-CoA synthetase 6.2.1.1; 6.2.1.13 TP04_0219
PEP/Pi translocator none TP01_0715

 

Open in a new window

 

 

Sources and fates of metabolites

 

Substrate Source pathways Product Fate pathways
Phosphoenolpyruvate Glycolysis Malate Host
L-Glutamate Glutamate metabolism Aspartate Glutamate metabolism
CoA CoA biosynthesis 2-oxoglutarate Tricarboxylic acid (TCA) cycle, Glutamate metabolism
Acetyl-CoA Tricarboxylic acid (TCA) cycle Acetyl-CoA Tricarboxylic acid (TCA) cycle