Purine metabolism (salvage)

The purine nucleotides are not only required as components of nucleic acids, but also as cofactors of metabolic processes and as a source of energy (ATP). Apicomplexa cannot synthesise purine rings de novo and salvage them from host. The putative transporters involved in the uptake of purine bases and nucleosides from parasitophorous vacuole are present in all apicomplexans including Toxoplasma gondii, Plasmodium falciparum and Cryptosporidium parvum. There were four transporters identified in T. gondii of which three are present in the genome of ME49 strain, whereas all four are present in VEG and GT1 strain genomes. In contrast, a single purine nucleotide transporter is present in Cryptosporidium species. It was identified as an ortholog of the adenosine transporter in C. parvum [1]. Cryptosporidium species possess limited set of enzymes involved in the salvage and inter-conversion of purines. Although an early study suggested the expression of hypoxanthine-xanthine-guanine phosphoribosyltransferase (HXGPRT) and adenine phosphoribosyltransferase (APRT) [2], both these enzymes are absent in all Cryptosporidium genomes sequenced. In addition, the treatment of C. parvum with 6-thioxanthine had no effect strongly suggesting the absence of HXGPRT [3]. All these suggest that adenosine is the only source of purine in Cryptosporidia. Adenosine kinase (AK) is present in the genomes of Cryptosporidia species. The transgenic expression of putative C. parvum adenosine kinase gene complements the enzymatic activity in the T. gondii AK null mutant [3]. Although the downstream enzymes involved in the inter-conversion of AMP to GMP (IMP dehydrogenase and GMP synthase) are missing in present gene models of Cryptosporidium muris, they are present in both C. parvum and Cryptosporidium hominis. The sensitivity and inhibition of development of C. parvum to IMP dehydrogenase inhibitors such as mycophenolic acid and ribavrin confirms the presence of this enzymatic activity. Unlike mammalian cells and T. gondii, IMP dehydrogenase is a potential drug target in C. parvum as this is the only route of guanine nucleotide synthesis [3].

 

Enzyme EC Number Gene id
IMP dehydrogenase 1.1.1.205 Missing in annotation
Ribonucleotide di-P reductase 1.17.4.1 CMU_007940
Ribonucleotide di-P reductase 1.17.4.1 CMU_027540
TRX reductase 1.8.1.9 CMU_002600
Adenosine kinase 2.7.1.20 CMU_026370
Adenylate kinase 2.7.4.3 CMU_000150
Adenylate kinase 2.7.4.3 CMU_015790
Nucleoside-diphosphate kinase 2.7.4.6 CMU_016590
Nucleoside-diphosphate kinase 2.7.4.6 CMU_040410
Guanylate kinase 2.7.4.8 CMU_034250
5'-nucleotidase 3.1.3.5 CMU_015700
3',5'-cyclic-nucleotide phosphodiesterase 3.1.4.17 CMU_001190
3',5'-cyclic-nucleotide phosphodiesterase 3.1.4.17 CMU_020730
3',5'-cyclic-nucleotide phosphodiesterase 3.1.4.17 CMU_027730
AMP deaminase 3.5.4.6 CMU_031490
Inorganic diphosphatase 3.6.1.1 CMU_028510
Ecto-nucleoside triphosphate diphosphohydrolase 3.6.1.15 CMU_018330
Nucleoside-triphosphate pyrophosphatase 3.6.1.19 CMU_001950
Apyrase 3.6.1.5 CMU_008360
Adenylate cyclase 4.6.1.1 CMU_009060
Adenylate cyclase 4.6.1.1 CMU_018220
Guanylate cyclase 4.6.1.2 CMU_042790
GMP synthase 6.3.5.2 Missing in annotation
Equilibrative nucleoside (adenosine) transporter none CMU_010240

 

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Sources and fates of metabolites

 

Substrate Source pathways Product Fate pathways
Adenosine Host dATP/dGTP DNA replication
    ATP/GTP Transcription, Many metabolic pathways
Glutamine Glutamate metabolism Glutamate Glutamate metabolism

 

 

Nucleoside catabolism

 

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