Purine and pyrimidine transport in pathogenic protozoa: From biology to therapy

Koning, Harry P. de; Bridges, Daniel J.; Burchmore, Richard

doi:10.1016/j.femsre.2005.03.004

Cited by 184 publications

(226 citation statements)

References 241 publications

(544 reference statements)

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“…The role of the P2-type purine transporter in the uptake of arsenical diamidines, pentamidine and DA by T. brucei, T. evansi and T. equiperdum, and the consequences of inhibition, knocking down or silencing this gene have been extensively described and reviewed in the literature [33], [34], [35], [36], [37], [38], [39], [40], [41], [42] and [43]. In addition to this resistance mechanism, a novel gene, TeDR40, might be a factor contributing to high DA-resistance in T. evansi [44].…”

Section: Resistance To Diminazene Aceturate By a P2-type Purine Transmentioning

confidence: 99%

Molecular tools for the rapid detection of drug resistance in animal trypanosomes

Delespaux

Geysen

Bossche

et al. 2008

Trends in Parasitology

103

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There are currently 17 African countries in which animal trypanocidal drug resistance has been reported. Largescale surveys were carried out in only ten of them. The lack of baseline information is mainly due to the fact that the methods currently available for the detection of drug resistance are laborious, expensive and time consuming. In this review the mechanisms involved in resistance to isometamidium and diminazene will be discussed, together with some new molecular detection tools that have been developed recently enabling faster diagnosis of drug resistance than conventional laboratory or field tests. African animal trypanosomiasis and drug resistanceTsetse fly-transmitted trypanosomiasis is an important constraint to livestock development in sub-Saharan Africa with estimated annual losses owing to the direct and indirect effects of the disease running into billions of dollars. Approximately 9 million km 2 of sub-Saharan Africa, representing about one-third of the total land, is affected by tsetse flies [1]. Within this region, some 46-62 million head of cattle and other livestock species are at risk of the disease [2]. Trypanosomiasis is controlled either by controlling the vector or by controlling the parasite, or a combination of both. Over the years, a large arsenal of vector-control tools has been developed. Nevertheless, the control of animal trypanosomiasis in often poor rural communities has and will continue to rely heavily on the use of trypanocidal drugs. This is not surprising considering the private nature (i.e. the easy, individual, nonconcerted use) of such treatments and the difficulties in maintaining cleared areas in the absence of barriers to re-invasion of tsetse flies. Only a small group of chemoprophylactic and chemotherapeutic trypanocidal compounds are currently in use and new compounds are unlikely to become available in the near future [3]. Geerts and Holmes [4] estimated that in Africa 35 million doses of veterinary trypanocidal drugs are administered each year with isometamidium chloride (ISM), ethidium bromide (EtBr) and diminazene aceturate (DA) estimated to represent 40%, 26% and 33%, respectively, of the total trypanocidal drug market by value [5]. ISM is mainly used as a prophylactic drug and provides on average 3 months' protection (2-22 weeks) against trypanosome infection. DA has only therapeutic properties and EtBr has limited prophylactic properties and is mainly used as a therapeutic agent [6]. Considering the well known mutagenic properties of EtBr, this drug should ideally be removed from the drug market, but in practice it is still widely used in many countries. Removing this drug from the market would not jeopardize the treatment of animal trypanosomiasis because it can be replaced either by DA for curative purposes or by ISM for prophylactic purposes. When trypanosomes are resistant to ISM, EtBr will be ineffective as cross-resistance is observed between the two drugs [7]. As a result of inappropriate trypanocidal drug-use practices, there is growing co...

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Section: Resistance To Diminazene Aceturate By a P2-type Purine Transmentioning

confidence: 99%

Molecular tools for the rapid detection of drug resistance in animal trypanosomes

Delespaux

Geysen

Bossche

et al. 2008

Trends in Parasitology

103

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“…Like virtually all growing and replicating cells, the intraerythrocytic parasite requires purines and pyrimidines for the synthesis of a range of important molecules including those involved in heredity (DNA), protein synthesis (RNA), bioenergetics (ATP, ADP) and cell signalling (cAMP, GTP). The malaria parasite, like other parasitic protozoa characterized to date, has the enzymes required for the de novo synthesis of pyrimidines, but lacks those for the synthesis of purines Landfear et al ., 2004;de Koning et al ., 2005); the growth of the intraerythrocytic malaria parasite is therefore reliant on the parasite salvaging purines from its external environment (Divo et al ., 1985).…”

Section: Introductionmentioning

confidence: 99%

Transport of nucleosides across the Plasmodium falciparum parasite plasma membrane has characteristics of PfENT1

Downie¹,

Saliba

Howitt³

et al. 2006

Molecular Microbiology

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SummaryLike all parasitic protozoa, the human malaria parasite Plasmodium falciparum lacks the enzymes required for de novo synthesis of purines and it is therefore reliant upon the salvage of these compounds from the external environment. P. falciparum equilibrative nucleoside transporter 1 (PfENT1) is a nucleoside transporter that has been localized to the plasma membrane of the intraerythrocytic form of the parasite. In this study we have characterized the transport of purine and pyrimidine nucleosides across the plasma membrane of 'isolated' trophozoite-stage P. falciparum parasites and compared the transport characteristics of the parasite with those of PfENT1 expressed in Xenopus oocytes. The transport of nucleosides into the parasite: (i) was, in the case of adenosine, inosine and thymidine, very fast, equilibrating within a few seconds; (ii) was of low affinity [ K m (adenosine) = 1.45 ± 0.25 mM; K m (thymidine) = 1.11 ± 0.09 mM]; and (iii) showed 'crosscompetition' for adenosine, inosine and thymidine, but not cytidine. The kinetic characteristics of nucleoside transport in intact parasites matched very closely those of PfENT1 expressed in Xenopus oocytes [ K m (adenosine) = 1.86 ± 0.28 mM; K m (thymidine) = 1.33 ± 0.17 mM]. Furthermore, PfENT1 transported adenosine, inosine and thymidine, with a cross-competition profile the same as that seen for isolated parasites. The data are consistent with PfENT1 serving as a major route for the uptake of nucleosides across the parasite plasma membrane.

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“…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.…”

mentioning

confidence: 99%

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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Purine and pyrimidine transport in pathogenic protozoa: From biology to therapy

Cited by 184 publications

References 241 publications

Molecular tools for the rapid detection of drug resistance in animal trypanosomes

Molecular tools for the rapid detection of drug resistance in animal trypanosomes

Transport of nucleosides across the Plasmodium falciparum parasite plasma membrane has characteristics of PfENT1

Erythrocytic Adenosine Monophosphate as an Alternative Purine Source in Plasmodium falciparum

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