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 reductase 1.17.4.1 CMU_007940
Ribonucleotide reductase 1.17.4.1 CMU_027540
TRX reductase 1.8.1.9 CMU_002600
Thymidylate synthetase 2.1.1.45 CMU_010300
Uracil phosphoribosyltransferase 2.4.2.9 CMU_036650
Bifunctional uracil phosphoribosyltransferase/uridine kinase 2.4.2.9; 2.7.1.48 CMU_026840
Thymidine kinase 2.7.1.21 CMU_038700
Cytidylate kinase 2.7.4.14 CMU_029940
Nucleoside-diphosphate kinase 2.7.4.6 CMU_016590
Nucleoside-diphosphate kinase 2.7.4.6 CMU_040410
dTMP kinase 2.7.4.9 CMU_010930
UTP-glucose-1-P uridylyltransferase 2.7.7.9 CMU_012960
UTP-glucose-1-P uridylyltransferase 2.7.7.9 CMU_033870
5'-nucleotidase 3.1.3.5 CMU_015700
dCMP deaminase 3.5.4.12 CMU_005200
Nucleoside-triphosphate pyrophosphatase 3.6.1.19 CMU_001950
dUTP diphosphatase 3.6.1.23 CMU_019310
CTP synthase 6.3.4.2 CMU_040120

 

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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