Pyrimidine metabolism (salvage)

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. All the six enzymes leading to de novo biosynthesis of UMP present in P. falciparum and T. gondii are absent in Cryptosporidium species.

 

There are three important pyrimidine salvage enzymes in Cryptosporidia. They are thymidine kinase (TK), a monofunctional uracil phosphoribosyltransferase (UPRT) enzyme and a bifunctional UPRT-uridine kinase (UK) enzyme. Of these the bifunctional UPRT-UK and thymidine kinase enzymes are absent in T. gondii and Neospora caninum, whereas all three salvage enzymes are absent in P. falciparum. The enzyme CTP synthase is present in all apicomplexans and is the only enzyme involved in the conversion of uridine to cytidine nucleotides. The enzyme cytidine deaminase present in both P. falciparum and T. gondii is absent in Cryptosporidia. Another salvage enzyme dCMP deaminase present in T.gondii and absent in P. falciparum is also present in Cryptosporidia. Pyrimidine (uridine) phosphorylase present in Toxoplasma is absent in both Plasmodia and Cryptosporidia. There are biochemical evidences for the expression of active thymidine kinase and uridine kinase enzymes. The presence of active TK was confirmed in Cryptosporidium parvum with bromodeoxyuridine incorporation [1]. Pronounced effects in parasite development seen with nucleoside analogs such as cytosine-arabinoside suggests the activity of uridine kinase [2].

 

Enzyme EC Number Gene id
Ribonucleotide di-P reductase 1.17.4.1 Chro.60090
Ribonucleotide reductase 1.17.4.1 Chro.60230
TRX reductase 1.8.1.9 Chro.20464
Thymidylate synthetase 2.1.1.45 Chro.40506
Uracil phosphoribosyltransferase 2.4.2.9 Chro.10216
Bifunctional uracil phosphoribosyltransferase/uridine kinase 2.4.2.9; 2.7.1.48 Chro.80328
Thymidine kinase 2.7.1.21 Chro.50398
Cytidylate kinase 2.7.4.14 Missing in annotation
Nucleoside-diphosphate kinase 2.7.4.6 Chro.40219
Nucleoside-diphosphate kinase 2.7.4.6 Chro.50237
dTMP kinase 2.7.4.9 Chro.50490
UTP-glucose-1-P uridylyltransferase 2.7.7.9 Chro.40100
UTP-glucose-1-P uridylyltransferase 2.7.7.9 Chro.70213
5'-nucleotidase 3.1.3.5 Chro.50026
dCMP deaminase 3.5.4.12 Chro.20294
Nucleoside-triphosphate pyrophosphatase 3.6.1.19 Chro.40472
dUTP diphosphatase 3.6.1.23 Chro.70577
CTP synthase 6.3.4.2 Chro.50211

 

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Sources and fates of metabolites

 

Substrate Source pathways Product Fate pathways
Uridine/Cytidine Host UTP/CTP Transcription, Many metabolic pathways
Uracil Host dTTP/dCTP DNA replication
Thymidine Host    
Glutamine Glutamate metabolism Glutamate Glutamate metabolism
Methylene-THF Recycling of folate DHF Recycling of folate