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]. The downstream enzymes involved in the inter-conversion of AMP to GMP (IMP dehydrogenase and GMP synthase) are also present in Cryptosporidium 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 cgd6_20
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
Adenosine kinase 2.7.1.20 cgd8_2370
Adenylate kinase 2.7.4.3 cgd3_3270
Adenylate kinase 2.7.4.3 cgd5_3360
Nucleoside-diphosphate kinase 2.7.4.6 cgd4_1940
Nucleoside-diphosphate kinase 2.7.4.6 cgd5_1470
Guanylate kinase 2.7.4.8 cgd7_2190
5'-nucleotidase 3.1.3.5 cgd5_3460
3',5'-cyclic-nucleotide phosphodiesterase 3.1.4.17 cgd3_2320
3',5'-cyclic-nucleotide phosphodiesterase 3.1.4.17 cgd6_4020
3',5'-cyclic-nucleotide phosphodiesterase 3.1.4.17 cgd6_500
AMP deaminase 3.5.4.6 cgd4_1890
Inorganic diphosphatase 3.6.1.1 cgd4_1400
Ecto-nucleoside triphosphate diphosphohydrolase 3.6.1.15 Missing in annotation
Nucleoside-triphosphate pyrophosphatase 3.6.1.19 cgd4_4150
Apyrase 3.6.1.5 cgd6_1570
Adenylate cyclase 4.6.1.1 cgd2_1270
Adenylate cyclase 4.6.1.1 cgd4_3100
Guanylate cyclase 4.6.1.2 cgd3_1110
GMP synthase 6.3.5.2 cgd5_4520
Equilibrative nucleoside (adenosine) transporter none cgd2_310

 

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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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