Tricarboxylic acid (TCA) cycle

Tricarboxylic acid cycle also called citrate cycle and Krebs cycle is the third step in aerobic respiration. In eukaryotes, this process takes place in the mitochondrial matrix. It utilises acetyl-CoA from pyruvate oxidation or fatty acid/protein degradation as substrate. In addition, each cycle utilises 2 H2O molecules and generates CO2 and coenzyme-A. This is a cycle of eight enzymes catalysing nine reactions where oxaloacetate, which reacts with acetyl-CoA in the first step, is replenished in the last step. The reverse of this cycle called reverse or reductive Krebs cycle also occurs in some bacteria which utilises CO2 and H2O to synthesise carbon compounds.

 

Genes for all the enzymes of this pathway are present in the Neospora caninum genome as in Toxoplasma gondii. Almost all of these enzymes are targeted to mitochondrion (either experimentally or bioinformatics predictions) in T. gondii [1, 2]. The only enzyme which is present in T. gondii and N. caninum and absent in Plasmodium falciparum is 2.3.3.8. Although the pyruvate dehydrogenase complex is present in the apicoplast in apicomplexans such as N. caninum, P. falciparum and T. gondii [3], the presence of complete pathways which catalyse generation of acetyl-CoA from fatty acids (fatty acid recycling and degradation) and branched chain amino acids (leucine, isoleucine and valine metabolism) suggests possible sources of acetyl-coA for Krebs cycle. This also suggests possible role of Krebs cycle in energy generation in at least some life cycle stages of T. gondii and N. caninum. The presence of anaplerotic enzymes which replenish oxaloacetate such as pyruvate carboxylase and PEP carboxykinase (pyruvate metabolism) suggests that Krebs cycle also has role in biosynthetic pathways. For more details on any available experimental evidence in Apicomplexa, refer to the TCA cycle pathway page for T. gondii.

 

Enzyme EC Number Gene id
Malate dehydrogenase 1.1.1.37 NCLIV_011120
Isocitrate dehydrogenase (ICDH2) 1.1.1.42 NCLIV_056480
Malate dehydrogenase (Quinone) 1.1.99.16 (Entry changed to 1.1.5.4) NCLIV_040970
Oxoglutarate dehydrogenase E1 subunit (part of oxoglutarate dehydrogenase complex) 1.2.4.2 NCLIV_018800
Succinate dehydrogenase 1.3.99.1 NCLIV_052230
Succinate dehydrogenase 1.3.99.1 NCLIV_052500
Succinate dehydrogenase 1.3.99.1 NCLIV_068970
Glutamate dehydrogenase 1.4.1.4 NCLIV_000130
Dihydrolipoamide dehydrogenase (part of oxoglutarate dehydrogenase complex) 1.8.1.4 NCLIV_044200
Dihydrolipoamide S-succinyl transferase (part of oxoglutarate dehydrogenase complex) 2.3.1.61 NCLIV_061040
Citrate (si)-synthase 2.3.3.1 NCLIV_021820
Citrate (si)-synthase 2.3.3.1 NCLIV_037460
ATP-citrate synthase 2.3.3.8 NCLIV_048670
Fumarate hydratase 4.2.1.2 NCLIV_038850
Aconitate hydratase 4.2.1.3 NCLIV_046260
Succinate-CoA ligase 6.2.1.4 NCLIV_042590
Succinate-CoA ligase 6.2.1.5 NCLIV_053880
Oxoglutarate/malate translocator none NCLIV_033680
Amino acid transporter none NCLIV_043960
Acetyl-CoA transporter none NCLIV_060190
Mitochondrial carrier protein none NCLIV_065050

 

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Sources and fates of metabolites

 

Substrate Source pathways Product Fate pathways
CoA Pantothenate and CoA biosynthesis Malate Host
Glutamate Glutamate metabolism Acetyl-CoA Pyruvate metabolism, Tricarboxylic acid (TCA) cycle, Fatty acid elongation in the cytosol, Fatty acid elongation in the ER
2-oxoglutarate Pyruvate metabolism    
Succinate 2-methylcitrate cycle