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 apicomplexans including Toxoplasma gondii, Plasmodium falciparum and Cryptosporidium parvum.

 

Piroplasma species possess limited set of enzymes involved in the salvage and inter-conversions of purines. The main purine salvaged by Babesia species is adenosine and the activities of some of the enzymes catalysing inter-conversions to AMP and GMP are detected in very early studies of Babesia divergens [1]. Matias et al also demonstrated the capability of synthesising adenosine and hypoxanthine into AMP and GMP in Babesia bovis [2] although the enzyme hypoxanthine-xanthine-guanine phosphoribosyltransferase (HXGPRT) is absent in the genomes of these species. The enzymes required for the conversion of adenosine to AMP and IMP such as adenosine deaminase and adenosine kinase are present in B. bovis genome, but missing in the gene models of Theileria parva and Theileria annulata. The enzymes catalysing the conversion of IMP to GMP and AMP are present in all Piroplasma species.

 

The toxicities of adenosine or deoxyadenosine analogues were tested in vitro against B. bovis. The comparison of the toxicity results to mammalian cell lines showed that many compounds relatively non-toxic towards mammalian cells are toxic towards Babesia. This shows the significant variation between transport, metabolism and incorporation into nucleic acids between Babesia and mammals [3]. This may also suggest the dependence of Babesia on adenosine alone as a source of purine rings and the potential of it as a drug target.

 

Enzyme EC Number Gene id
IMP dehydrogenase 1.1.1.205 BBOV_IV006900
Ribonucleotide di-P reductase 1.17.4.1 BBOV_I004870
Ribonucleotide di-P reductase 1.17.4.1 BBOV_IV006460
Ribonucleotide di-P reductase 1.17.4.1 BBOV_IV010610
GMP reductase 1.7.1.7 BBOV_IV005560
TRX reductase 1.8.1.9 BBOV_I002190
Purine nucleoside phosphorylase 2.4.2.1 BBOV_III005140
Purine nucleoside phosphorylase 2.4.2.1 BBOV_III005150
Adenosine kinase 2.7.1.20 BBOV_IV003810
Adenosine kinase 2.7.1.20 BBOV_IV003860
Adenylate kinase 2.7.4.3 BBOV_II007510
Adenylate kinase 2.7.4.3 BBOV_IV008100
Adenylate kinase 2.7.4.3 BBOV_IV002930
Nucleoside-diphosphate kinase 2.7.4.6 BBOV_III005290
Guanylate kinase 2.7.4.8 BBOV_II006160
3',5'-cyclic-nucleotide phosphodiesterase 3.1.4.17 BBOV_IV006510
3',5'-cyclic-nucleotide phosphodiesterase 3.1.4.17 BBOV_IV010070
Adenosine deaminase 3.5.4.4 BBOV_I001470
Inorganic diphosphatase 3.6.1.1 BBOV_III010840
Ecto-nucleoside triphosphate diphosphohydrolase 3.6.1.15 BBOV_I001910
Ecto-nucleoside triphosphate diphosphohydrolase 3.6.1.15 BBOV_II004720
Ecto-nucleoside triphosphate diphosphohydrolase 3.6.1.15 BBOV_III000620
Ecto-nucleoside triphosphate diphosphohydrolase 3.6.1.15 BBOV_III000640
Nucleoside-triphosphate pyrophosphatase 3.6.1.19 BBOV_III001450
Adenylosuccinate lyase 4.3.2.2 BBOV_III000760
Adenylate cyclase 4.6.1.1 BBOV_IV007360
Guanylate cyclase 4.6.1.2 BBOV_I000770
Adenylosuccinate synthase 6.3.4.4 BBOV_II004950
GMP synthase 6.3.5.2 BBOV_IV009110

 

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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 Host Glutamate Glutamate metabolism
Aspartate Glutamate metabolism Fumarate Tricarboxylic acid (TCA) cycle




Nucleoside catabolism

 

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