Xanthine oxidase inhibits growth of Plasmodium falciparum in human erythrocytes in vitro.

Berman, Peter; Human, L.; Freese, Janet A.

doi:10.1172/jci115506

Cited by 49 publications

(40 citation statements)

References 28 publications

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“…Purines must be added to culture media for robust parasite growth in vitro. Removal of exogenous purines and/or the presence of xanthine oxidase to remove hypoxanthine stops parasite growth in culture (36). Blocking both human and Plasmodium PNP with DADMeImmG in the absence of exogenous purines killed cultured parasites, but ADA inhibition with coformycin and AK inhibition with ITU at a 1:1 molar ratio did not augment the effect of PNP inhibition.…”

Section: Discussionmentioning

confidence: 98%

Erythrocytic Adenosine Monophosphate as an Alternative Purine Source in Plasmodium falciparum

Cassera

Hazleton

Riegelhaupt

et al. 2008

Journal of Biological Chemistry

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Plasmodium falciparum is a purine auxotroph, salvaging purines from erythrocytes for synthesis of RNA and DNA. Hypoxanthine is the key precursor for purine metabolism in Plasmodium. Inhibition of hypoxanthine-forming reactions in both erythrocytes and parasites is lethal to cultured P. falciparum. We observed that high concentrations of adenosine can rescue cultured parasites from purine nucleoside phosphorylase and adenosine deaminase blockade but not when erythrocyte adenosine kinase is also inhibited. P. falciparum lacks adenosine kinase but can salvage AMP synthesized in the erythrocyte cytoplasm to provide purines when both human and Plasmodium purine nucleoside phosphorylases and adenosine deaminases are inhibited. Transport studies in Xenopus laevis oocytes expressing the P. falciparum nucleoside transporter PfNT1 established that this transporter does not transport AMP. These metabolic patterns establish the existence of a novel nucleoside monophosphate transport pathway in P. falciparum.Malaria is one of the leading causes of morbidity and mortality in the tropics with 300 -500 million clinical cases and 1.5-2.7 million deaths per year (1). Malaria is caused by protozoan parasites of the Plasmodium genus of which Plasmodium falciparum is responsible for most of the fatal cases. The parasite is transmitted between human hosts by Anopheles mosquitoes. Malaria has been treated for many years through chemotherapeutic and vector control strategies, but these have not prevented widespread occurrence. An alarming increase in both the resistance of malaria parasites to drug treatment and in mosquito vectors to insecticides has renewed the demand for the development of new chemotherapeutic strategies (2, 3). Advances in the knowledge of the metabolic and nutritional needs of the parasite offer new potential routes for chemotherapy. Because of the rapid rate of DNA synthesis during the 48-h intraerythrocytic growth phase, targeting purine metabolic pathways is a promising route for novel drug development.P. falciparum is a purine auxotroph, salvaging host cell purines for synthesis of cofactors and nucleic acids (4, 5). Purine nucleosides and nucleobases can be transported across the parasite plasma membrane by the PfNT1 2 transporter (Fig. 1). The mechanisms by which Plasmodium salvages purines during the intraerythrocytic cycle are diverse both with regard to primary sources and to routes of interconversion (Fig. 1). Hypoxanthine is the key precursor of other purines in Plasmodium metabolism and is commonly used as a nutritional supplement in malarial culture media. A key source of hypoxanthine in vivo is from the erythrocyte purine pool where ATP is in dynamic metabolic exchange with hypoxanthine via ADP, AMP, IMP, inosine, and adenosine (5). In human erythrocytes, adenosine is efficiently salvaged by adenosine kinase (hAK). This allows human erythrocytes to utilize serum adenosine to maintain erythrocyte ATP levels. In P. falciparum, adenosine is salvaged by conversion to hypoxanthine using adenosine deaminas...

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Section: Discussionmentioning

confidence: 98%

Erythrocytic Adenosine Monophosphate as an Alternative Purine Source in Plasmodium falciparum

Cassera

Hazleton

Riegelhaupt

et al. 2008

Journal of Biological Chemistry

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“…We believe that this specific interaction of spirochetes with erythrocytes could provide a mechanism for the direct uptake of hypoxanthine, which is utilized for the synthesis of both RNA and DNA nucleotides. The human malarial parasite Plasmodium falciparum is also unable to synthesize purines de novo and relies on the salvage of intraerythrocytic hypoxanthine for its purine source to synthesize nucleotides (7,18). The direct uptake of hypoxanthine by the relapsing fever spirochetes from the outer surface of red blood cells could account, in part, for the ability of these spirochetes to achieve such high cell densities in the blood, and efforts to test this hypothesis are under way.…”

Section: Discussionmentioning

confidence: 99%

Purine Salvage Pathways among Borrelia Species

Pettersson¹,

Schrumpf²,

Raffel³

et al. 2007

Infect Immun

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Genome sequencing projects on two relapsing fever spirochetes, Borrelia hermsii and Borrelia turicatae, revealed differences in genes involved in purine metabolism and salvage compared to those in the Lyme disease spirochete Borrelia burgdorferi. The relapsing fever spirochetes contained six open reading frames that are absent from the B. burgdorferi genome. These genes included those for hypoxanthine-guanine phosphoribosyltransferase (hpt), adenylosuccinate synthase (purA), adenylosuccinate lyase (purB), auxiliary protein (nrdI), the ribonucleotide-diphosphate reductase alpha subunit (nrdE), and the ribonucleotide-diphosphate reductase beta subunit (nrdF). Southern blot assays with multiple Borrelia species and isolates confirmed the presence of these genes in the relapsing fever group of spirochetes but not in B. burgdorferi and related species. TaqMan real-time reverse transcription-PCR demonstrated that the chromosomal genes (hpt, purA, and purB) were transcribed in vitro and in mice. Phosphoribosyltransferase assays revealed that, in general, B. hermsii exhibited significantly higher activity than did the B. burgdorferi cell lysate, and enzymatic activity was observed with adenine, hypoxanthine, and guanine as substrates. B. burgdorferi showed low but detectable phosphoribosyltransferase activity with hypoxanthine even though the genome lacks a discernible ortholog to the hpt gene in the relapsing fever spirochetes. B. hermsii incorporated radiolabeled hypoxanthine into RNA and DNA to a much greater extent than did B. burgdorferi. This complete pathway for purine salvage in the relapsing fever spirochetes may contribute, in part, to these spirochetes achieving high cell densities in blood.

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“…Furthermore, malaria parasites grow poorly in vitamin E-deficient mice (28). ROS-generating systems kill murine malaria parasites in vitro (10,26,27) and in vivo (14,15,16) and kill Plasmodium falciparum in vitro (7,13,45,72).…”

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confidence: 99%

Phagocyte-Derived Reactive Oxygen Species Do Not Influence the Progression of Murine Blood-Stage Malaria Infections

et al. 2005

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Phagocyte-derived reactive oxygen species have been implicated in the clearance of malaria infections. We investigated the progression of five different strains of murine malaria in gp91 phox؊/؊ mice, which lack a functional NADPH oxidase and thus the ability to produce phagocyte-derived reactive oxygen species. We found that the absence of functional NADPH oxidase in the gene knockout mice had no effect on the parasitemia or total parasite burden in mice infected with either resolving (Plasmodium yoelii and Plasmodium chabaudi K562) or fatal (Plasmodium berghei ANKA, Plasmodium berghei K173 and Plasmodium vinckei vinckei) strains of malaria. This lack of effect was apparent in both primary and secondary infections with P. yoelii and P. chabaudi. There was also no difference in the presentation of clinical or pathological signs between the gp91 phox؊/؊ or wild-type strains of mice infected with malaria. Progression of P. berghei ANKA and P. berghei K173 infections was unchanged in glutathione peroxidase-1 gene knockout mice compared to their wild-type counterparts. The rates of parasitemia progression in gp91 phox؊/؊ mice and wild-type mice were not significantly different when they were treated with L-N G -methylarginine, an inhibitor of nitric oxide synthase. These results suggest that phagocyte-derived reactive oxygen species are not crucial for the clearance of malaria parasites, at least in murine models.

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Xanthine oxidase inhibits growth of Plasmodium falciparum in human erythrocytes in vitro.

Cited by 49 publications

References 28 publications

Erythrocytic Adenosine Monophosphate as an Alternative Purine Source in Plasmodium falciparum

Erythrocytic Adenosine Monophosphate as an Alternative Purine Source in Plasmodium falciparum

Purine Salvage Pathways among Borrelia Species

Phagocyte-Derived Reactive Oxygen Species Do Not Influence the Progression of Murine Blood-Stage Malaria Infections

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