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 cgd6_690
Ribonucleotide reductase 1.17.4.1 cgd6_1950
TRX reductase 1.8.1.9 cgd2_4320
Thymidylate synthetase 2.1.1.45 cgd4_4460
Uracil phosphoribosyltransferase 2.4.2.9 cgd1_1900
Bifunctional uracil phosphoribosyltransferase/uridine kinase 2.4.2.9; 2.7.1.48 cgd8_2810
Thymidine kinase 2.7.1.21 cgd5_4440
Cytidylate kinase 2.7.4.14 cgd1_3140
Nucleoside-diphosphate kinase 2.7.4.6 cgd4_1940
Nucleoside-diphosphate kinase 2.7.4.6 cgd5_1470
dTMP kinase 2.7.4.9 cgd5_3630
UTP-glucose-1-P uridylyltransferase 2.7.7.9 cgd4_810
UTP-glucose-1-P uridylyltransferase 2.7.7.9 cgd7_1830
5'-nucleotidase 3.1.3.5 cgd5_3460
dCMP deaminase 3.5.4.12 cgd2_2780
Nucleoside-triphosphate pyrophosphatase 3.6.1.19 cgd4_4150
dUTP diphosphatase 3.6.1.23 cgd7_5170
CTP synthase 6.3.4.2 cgd5_1710
Enhancer of rudimentary none cgd2_3910

 

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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