Plasmodium vivax hypoxanthine-guanine phosphoribosyltransferase: A target for anti-malarial chemotherapy

Keough, Dianne T.; Hocková, Dana; Krečmerová, Marcela; Česnek, Michal; Holý, Antonı́n; Naesens, Lieve; Brereton, Ian M.; Winzor, Donald J.; Jersey, John de; Guddat, L.W.

doi:10.1016/j.molbiopara.2010.05.018

Cited by 36 publications

(30 citation statements)

References 18 publications

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“…1B). [10][11][12] Since highly conserved regions of amino acid residues are involved in the catalysis, cocrystal structures 9 of ANPs interacting with the active site of human HGPRT provides an excellent model to design suitable new inhibitors. Based on these insights, we have been able to synthesize new compounds that can, with a high degree of complementarity, precisely fill the active site of PRTases.…”

Section: Introductionmentioning

confidence: 99%

Antimalarial activity of prodrugs of N-branched acyclic nucleoside phosphonate inhibitors of 6-oxopurine phosphoribosyltransferases

Hocková

Janeba

Naesens

et al. 2015

Bioorganic & Medicinal Chemistry

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Acyclic nucleoside phosphonates (ANPs) that contain a 6-oxopurine base are good inhibitors of the human and Plasmodium falciparum 6-oxopurine phosphoribosyltransferases (PRTs), key enzymes of the purine salvage pathway. Chemical modifications, based on the crystal structures of several inhibitors in complex with the human PRTase, led to the design of a new class of inhibitors -the aza-ANPs. Because of the negative charges of the phosphonic acid moiety, their ability to cross cell membranes is, however, limited. Thus, phosphoramidate prodrugs of the aza-ANPs were prepared to improve permeability. These prodrugs arrest parasitemia with IC 50 values in the micromolar range against Plasmodium falciparum-infected erythrocyte cultures (both chloroquine-sensitive and chloroquine-resistant Pf strains). The prodrugs exhibit low cytotoxicity in several human cell lines. Thus, they fulfill two essential criteria to qualify them as promising antimalarial drug leads.

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Section: Introductionmentioning

confidence: 99%

Antimalarial activity of prodrugs of N-branched acyclic nucleoside phosphonate inhibitors of 6-oxopurine phosphoribosyltransferases

Hocková

Janeba

Naesens

et al. 2015

Bioorganic & Medicinal Chemistry

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“…While humans exploit both these pathways, protozoan parasites like Plasmodium, Leshmania, Tritrichomonas and Trypanosoma lack the de novo synthesis of nucleotides and rely solely on their ability to salvage free nucleobases into nucleotides. Thus, enzymes of the salvage pathway are identified as potential therapeutic targets against these parasites [1][2][3][4]. Therapeutic intervention that targets these enzymes requires development of effective analogues of the natural substrates and on-enzyme intermediates [5,6].…”

Section: Introductionmentioning

confidence: 99%

Solution structure of ligands involved in purine salvage pathway

Karnawat

Puranik

2015

Spectrochimica Acta Part A: Molecular and Biomolecular Spectros

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“…Similarly, the purine salvage pathway has also been investigated in numerous organisms (42,55). PRTases, the enzymes capable of joining salvaged purine bases with PRPP in order to generate purine nucleotides, have also been studied in numerous pathogens (17,18,38,39).…”

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Helicobacter pylori Relies Primarily on the Purine Salvage Pathway for Purine Nucleotide Biosynthesis

Liechti

Goldberg

2012

J Bacteriol

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Helicobacter pylori is a chronic colonizer of the gastric epithelium and plays a major role in the development of gastritis, peptic ulcer disease, and gastric cancer. In its coevolution with humans, the streamlining of the H. pylori genome has resulted in a significant reduction in metabolic pathways, one being purine nucleotide biosynthesis. Bioinformatic analysis has revealed that H. pylori lacks the enzymatic machinery for de novo production of IMP, the first purine nucleotide formed during GTP and ATP biosynthesis. This suggests that H. pylori must rely heavily on salvage of purines from the environment. In this study, we deleted several genes putatively involved in purine salvage and processing. The growth and survival of these mutants were analyzed in both nutrient-rich and minimal media, and the results confirmed the presence of a robust purine salvage pathway in H. pylori. Of the two phosphoribosyltransferase genes found in the H. pylori genome, only gpt appears to be essential, and an ⌬apt mutant strain was still capable of growth on adenine, suggesting that adenine processing via Apt is not essential. Deletion of the putative nucleoside phosphorylase gene deoD resulted in an inability of H. pylori to grow on purine nucleosides or the purine base adenine. Our results suggest a purine requirement for growth of H. pylori in standard media, indicating that H. pylori possesses the ability to utilize purines and nucleosides from the environment in the absence of a de novo purine nucleotide biosynthesis pathway. Helicobacter pylori is a Gram-negative, microaerophilic helixshaped bacterium that colonizes the gastric mucosa of roughly half of the world's population (19,53). Unlike numerous other pathogenic bacteria capable of existing in diverse environmental niches, H. pylori is only capable of sustained growth within its human host (19). Identified only 27 years ago (45), this bacterium was the first to have two different strains sequenced, allowing for the first genome-wide comparative bioinformatic analysis of a bacterial species (1, 16). The results of this comparative sequencing project (16) as well as subsequent sequencing projects (3) show a relatively small genome with numerous alterations in its metabolic pathways compared with those of other bacterial species. Initial conclusions were that the missing pathway enzymes simply were divergent enough to escape classification by homology screening (16); however, subsequent analysis of the genome has identified 48 potential "dead-end metabolites" (metabolites only consumed or only produced within a metabolic network), indicating missing knowledge about a particular pathway or absence of a fully functional pathway (67). One hypothesis developed to explain these abnormalities was that, having evolved alongside humans for so long, the metabolism of H. pylori was streamlined to coexist in the human niche. Apparent holes in the metabolic pathways of H. pylori suggest the loss of genes no longer required for growth in its relatively stable environment of the huma...

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Plasmodium vivax hypoxanthine-guanine phosphoribosyltransferase: A target for anti-malarial chemotherapy

Cited by 36 publications

References 18 publications

Antimalarial activity of prodrugs of N-branched acyclic nucleoside phosphonate inhibitors of 6-oxopurine phosphoribosyltransferases

Antimalarial activity of prodrugs of N-branched acyclic nucleoside phosphonate inhibitors of 6-oxopurine phosphoribosyltransferases

Solution structure of ligands involved in purine salvage pathway

Helicobacter pylori Relies Primarily on the Purine Salvage Pathway for Purine Nucleotide Biosynthesis

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