Pyrimidine metabolism (biosynthesis)

The apicomplexans Toxoplasma gondii and Plasmodium falciparum can synthesise pyrimidine de novo from aspartate and glutamine. The Cryptosporidium species cannot synthesise pyrimidines de novo and salvages it from host. T. gondii also possess the salvage mechanisms in addition to de novo synthesis, whereas P. falciparum does not possess salvaging ability. The Piroplasma species possess the capability to synthesise pyrimidines de novo and cannot salvage pyrimidines from host. This suggests that they are similar to Plasmodium species when compared to the Coccidia. The presence of five of six enzymes of UMP biosynthesis pathway was shown to be conclusively present in Babesia rodhaini from the measurement of their specific activities [1]. The activities of all the six enzymes had been demonstrated in Babesia bovis and Babesia bigemina by Gero et al. The specific activities of the Babesia enzymes were of the same order of magnitude to the enzymes of the rodent malaria parasite Plasmodium berghei [2].

 

The genes for these six enzymes of de novo biosynthesis are present in the genomes of both Theileria species and B. bovis. The enzyme CTP synthase is present in all apicomplexans including Piroplasma species and is the only enzyme involved in the conversion of uridine to cytidine nucleotides. In addition to these, the enzyme cytidine/dCTP deaminase, an enzyme involved in deamination of dCTP to dUTP is present in Plasmodium, Toxoplasma and Piroplasma species. Other salvage enzymes present in T. gondii and absent in P. falciparum such as dCMP deaminase, uracil phosphoribosyltransferase (UPRT) and pyrimidine (uridine) phosphorylase are absent in these species.

 

Enzyme EC Number Gene id
Ribonucleotide di-P reductase 1.17.4.1 TP01_0725
Ribonucleotide di-P reductase 1.17.4.1 TP01_1196
Ribonucleotide di-P reductase 1.17.4.1 TP03_0528
Dihydroorotate dehydrogenase 1.3.5.2 TP02_0171
TRX reductase 1.8.1.9 TP03_0110
Thymidylate synthetase 2.1.1.45 TP04_0504
Aspartate carbamoyltransferase 2.1.3.2 TP01_0476
Orotate phosphoribosyl transferase 2.4.2.10 TP01_0073
Cytidylate kinase 2.7.4.14 TP02_0690
Nucleoside-diphosphate kinase 2.7.4.6 TP02_0422
dTMP kinase 2.7.4.9 TP02_0319
UTP-glucose-1-P uridylyltransferase 2.7.7.9 TP01_0489
Dihydroorotase 3.5.2.3 TP04_0882
Cytidine deaminase/dCTP deaminase 3.5.4.5; 3.5.4.13 TP03_0793
Nucleoside-triphosphate pyrophosphatase 3.6.1.19 TP03_0695
dUTP diphosphatase 3.6.1.23 TP01_0381
Orotidine-5'-phosphate decarboxylase 4.1.1.23 TP01_1133
Carbonic anhydrase 4.2.1.1 TP02_0412
CTP synthase 6.3.4.2 TP02_0838
Carbamoyl-P synthase 6.3.5.5 TP03_0048

 

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Sources and fates of metabolites

 

Substrate Source pathways Product Fate pathways
Glutamine Host Glutamate Glutamate metabolism
Aspartate Glutamate metabolism UTP/CTP Transcription, Many metabolic pathways
PRPP Pentose phosphate cycle dTTP/dCTP DNA replication
Methylene-THF Recycling of folate DHF Recycling of folate