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 TA05060
Ribonucleotide di-P reductase 1.17.4.1 TA06715
Ribonucleotide di-P reductase 1.17.4.1 TA09665
Dihydroorotate dehydrogenase 1.3.5.2 TA11695
TRX reductase 1.8.1.9 TA04645
Thymidylate synthetase 2.1.1.45 TA08775
Aspartate carbamoyltransferase 2.1.3.2 TA20650
Orotate phosphoribosyl transferase 2.4.2.10 TA19940
Cytidylate kinase 2.7.4.14 TA14600
Nucleoside-diphosphate kinase 2.7.4.6 TA13095
dTMP kinase 2.7.4.9 TA12510
UTP-glucose-1-P uridylyltransferase 2.7.7.9 TA20605
Dihydroorotase 3.5.2.3 TA11110
Cytidine deaminase/dCTP deaminase 3.5.4.5; 3.5.4.13 TA18255
Nucleoside-triphosphate pyrophosphatase 3.6.1.19 TA17785
dUTP diphosphatase 3.6.1.23 TA20975
Orotidine-5'-phosphate decarboxylase 4.1.1.23 TA16510
Carbonic anhydrase 4.2.1.1 TA13045
CTP synthase 6.3.4.2 TA15425
Carbamoyl-P synthase 6.3.5.5 TA02545

 

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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