Pyruvate metabolism

Although, pyruvate metabolism pathway here is similar to the pathway in MPMP (http://sites.huji.ac.il/malaria/maps/pyruvatemetpath.html), there are two exceptions. The first is that MPMP pathway possess phosphoenolpyruvate carboxylase enzyme, which is absent in T. gondii. The PEP carboxylase enzyme is replaced by pyruvate carboxylase in T. gondii, which is absent in Plasmodium falciparum. The second exception is that P. falciparum has no capability to synthesise alanine from pyruvate, which is present in T. gondii. The pathway of pyruvate metabolism in T. gondii has four separate components, of which the first three are present in P. falciparum.

 

  1. Pyruvate oxidation into acetyl-CoA – There are two isoforms of the enzyme pyruvate kinase in P. falciparum and T. gondii, 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 (both Toxoplasma and Plasmodium), PEP carboxylase (Plasmodium) 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. The enzymes aspartate transaminase and malate dehydrogenase present in Plasmodium 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 T. gondii and P. falciparum.
  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. It is a metabolic capability unique to Coccidians such as Toxoplasma and Neospora and absent in other apicomplexans.

 

Protein EC Number Gene id Protein localisation Localisation data source
Acetoacetyl-CoA reductase 1.1.1.36 TGME49_260460    
Malate dehydrogenase 1.1.1.37 TGME49_318430 Mitochondrion Apiloc
Pyruvate dehydrogenase E1 alpha subunit (part of pyruvate dehydrogenase complex) 1.2.4.1 TGME49_245670 Apicoplast Apiloc; Previous publication; Orthology transformation from P. falciparum
Pyruvate dehydrogenase E1 beta subunit (part of pyruvate dehydrogenase complex) 1.2.4.1 TGME49_272290 Apicoplast Apiloc; Previous publication
Alanine dehydrogenase 1.4.1.1 TGME49_203500    
Alanine dehydrogenase 1.4.1.1 TGME49_315260    
Dihydrolipoyl dehydrogenase (part of pyruvate dehydrogenase complex) 1.8.1.4 TGME49_305980 Apicoplast Apiloc; Previous publication; Orthology transformation from P. falciparum
Dihydrolipoamide S-acetyltransferase (part of pyruvate dehydrogenase complex) 2.3.1.12 TGME49_206610 Apicoplast Apiloc; Previous publication; Orthology transformation from P. falciparum
Peptide a-N-acetyltransferase 2.3.1.88 TGME49_219760    
Peptide a-N-acetyltransferase 2.3.1.88 TGME49_289900    
Acetyl-CoA C-acetyltransferase 2.3.1.9 TGME49_301120 Mitochondrion Previous publication
Aspartate transaminase 2.6.1.1 TGME49_248600 Cytosol Previous publication
Alanine transaminase 2.6.1.2 TGME49_264030    
Pyruvate kinase 2.7.1.40 TGME49_256760 Cytosol; Inner membrane complex; Apicoplast Apiloc; Previous publication
Pyruvate kinase 2.7.1.40 TGME49_299070 Apicoplast; Mitochondrion; Endoplasmic reticulum Apiloc; Previous publication; Orthology transformation from P. falciparum
PEP carboxykinase 4.1.1.49 TGME49_289650 Cytosol; Mitochondrion Apiloc; Previous publication
PEP carboxykinase 4.1.1.49 TGME49_289930    
Carbonic anhydrase 4.2.1.1 TGME49_259950 Nucleus Previous publication
Carbonic anhydrase 4.2.1.1 TGME49_297070 Plasma membrane Previous publication
Acetate-CoA ligase/Acetyl-CoA synthetase 6.2.1.1; 6.2.1.13 TGME49_232580    
Acetate-CoA ligase/Acetyl-CoA synthetase 6.2.1.1; 6.2.1.13 TGME49_266640 Mitochondrion Previous publication
Pyruvate carboxylase 6.4.1.1 TGME49_284190    
Acetyl-CoA transporter none TGME49_215940 Plasma membrane Previous publication
PEP/Pi translocator none TGME49_261070 Apicoplast membrane; Apicoplast GO annotation; Apiloc

 

Open in a new window

 

 

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