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Uptake of purines in <i>Plasmodium falciparum</i>-infected human erythrocytes is mostly mediated by the human Equilibrative Nucleoside Transporter and the human Facilitative Nucleobase Transporter

By N.B. Quashie, L.C. Ranford-Cartwright and H.P. De Koning


<b>Background</b>: Plasmodium parasites are unable to synthesize purines de novo and have to salvage them from the host. Due to this limitation in the parasite, purine transporters have been an area of focus in the search for anti-malarial drugs. Although the uptake of purines through the human equilibrative nucleoside transporter (hENT1), the human facilitative nucleobase transporter (hFNT1) and the parasite-induced new permeation pathway (NPP) has been studied, no information appears to exist on the relative contribution of these three transporters to the uptake of adenosine and hypoxanthine. Using the appropriate transporter inhibitors, the role of each of these salvage pathways to the overall purine transport in intraerythrocytic Plasmodium falciparum was systematically investigated.\ud \ud <b>Methods</b>: The transport of adenosine, hypoxanthine and adenine into uninfected and P. falciparum-infected human erythrocytes was investigated in the presence or absence of classical inhibitors of the hFNT1, hENT1 and NPP. The effective inhibition of the various transporters by the classical inhibitors was verified using appropriate known substrates. The ability of high concentration of unlabelled substrates to saturate these transporters was also studied.\ud \ud <b>Results</b>: Transport of exogenous purine into infected or uninfected erythrocytes occurred primarily through saturable transporters rather than through the NPP. Hypoxanthine and adenine appeared to enter erythrocytes mainly through the hFNT1 nucleobase transporter whereas adenosine entered predominantly through the hENT1 nucleoside transporter. The rate of purine uptake was approximately doubled in infected cells compared to uninfected erythrocytes. In addition, it was found that the rate of adenosine uptake was considerably higher than the rate of hypoxanthine uptake in infected human red blood cells (RBC). It was also demonstrated that furosemide inhibited the transport of purine bases through hFNT1.\ud \ud <b>Conclusion</b>: Collectively, the data obtained in this study clearly show that the endogenous host erythrocyte transporters hENT1 and hFNT1, rather than the NPP, are the major route of entry of purine into parasitized RBC. Inhibitors of hENT1 and hFNT1, as well as the NPP, should be considered in the development of anti-malarials targeted to purine transport

Topics: QR
Publisher: BioMed Central
Year: 2010
OAI identifier:
Provided by: Enlighten

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  1. (1971). A mediated process in human erythrocytes. doi
  2. (2000). A voltage-dependent channel involved in nutrient uptake by red blood cells infected with the malaria parasite. Nature
  3. (1991). BM: Uridine transport in human erythrocytes: data from normal subjects and from patients with renal failure. Exp Physiol
  4. (2005). Burchmore RJ: Purine and pyrimidine transport in pathogenic protozoa: from biology to therapy. FEMS Microbiol Rev doi
  5. (1987). Cabantchik ZI: Covalent modification of the permeability pathways induced in the human erythrocyte membrane by the malarial parasite Plasmodium falciparum. doi
  6. (1983). Cabantchik ZI: New permeability pathways induced in membranes of Plasmodium falciparum infected erythrocytes. Mol Biochem Parasitol doi
  7. (1986). Cardiovascular effects of adenosine in man; possible clinical implications. Prog Neurobiol doi
  8. (1989). Christopherson RI: Antimalarial action of nitrobenzylthioinosine in combination with purine nucleoside antimetabolites. Mol Biochem Parasitol doi
  9. (1994). CI: Transport of diverse substrates into malaria-infected erythrocytes via a pathway showing functional characteristics of a chloride channel.
  10. (1982). Concentration of Plasmodium falciparuminfected erythrocytes by density gradient centrifugation in Percoll. doi
  11. (2008). De Koning HP: A comprehensive model of purine uptake by the malaria parasite Plasmodium falciparum: identification of four purine transport activities in intraerythrocytic parasites. doi
  12. (2002). de Koning HP: Different substrate recognition motifs of human and trypanosome nucleobase transporters. Selective uptake of purine antimetabolites. doi
  13. (2006). Ellory JC: Solute transport via the new permeability pathways in Plasmodium falciparuminfected human red blood cells is not consistent with a simple singlechannel model. Blood doi
  14. (1981). Facilitated transport of inosine and uridine in cultured mammalian cells is independent of nucleoside phosphorylases. Biochim Biophys Acta doi
  15. (1991). Freese JA: Xanthine oxidase inhibits growth of Plasmodium falciparum in human erythrocytes in vitro. doi
  16. (1995). Gero AM: Parasite-induced permeation of nucleosides in Plasmodium falciparum malaria. Biochim Biophys Acta doi
  17. (1988). GP: Stage-specific alteration of nucleoside membrane permeability and nitrobenzylthioinosine insensitivity in Plasmodium falciparum infected erythrocytes. Mol Biochem Parasitol doi
  18. (1982). HG: Enzymes of purine and pyrimidine metabolism from the human malaria parasite, Plasmodium falciparum. Mol Biochem Parasitol doi
  19. (1995). Horner HA: In search of a selective inhibitor of the induced transport of small solutes in Plasmodium falciparum-infected erythrocytes: effects of arylaminobenzoates.
  20. (1991). Human L: Hypoxanthine depletion induced by xanthine oxidase inhibits malaria parasite growth in vitro. Adv Exp Med Biol doi
  21. (1976). Human malaria parasites in continuous culture. Science doi
  22. (2000). Isolation and functional characterization of the PfNT1 nucleoside transporter gene from Plasmodium falciparum. doi
  23. (2002). Lang F: Plasmodium falciparum activates endogenous Cl(-) channels of human erythrocytes by membrane oxidation.
  24. (2006). Mamoun C: The plasma membrane permease PfNT1 is essential for purine salvage in the human malaria parasite Plasmodium falciparum. Proc Natl Acad Sci USA doi
  25. (1984). Measurement of adenosine, inosine, and hypoxanthine in human plasma. doi
  26. (2000). Nucleobase transporters (review). Mol Membr Biol doi
  27. (1988). Nucleoside and nucleobase transport in animal cells. Biochim Biophys Acta doi
  28. (1967). Nukleinsäurenstoffwechsel bei experimenteller Malaria 2. Einbau von Adenosin und Hypoxanthin in die Nukleinsäuren Quashie et al.
  29. (2008). Purine nucleobase transport in the intraerythrocytic malaria parasite. doi
  30. (2000). SA: Identification of a nucleoside/nucleobase transporter from Plasmodium falciparum, a novel target for anti-malarial chemotherapy. doi
  31. (2006). SA: Specific inhibition of the plasmodial surface anion channel by dantrolene. Eukaryot Cell doi
  32. (1997). ST: Plasmodium falciparum: transport of entantiomers of nucleosides into Sendai-treated trophozoites. Exp Parasitol doi
  33. (1988). TP: Purine nucleobase transport in human erythrocytes. Reinvestigation with a novel “inhibitor-stop” assay.
  34. (1998). Transport and metabolism of the essential vitamin pantothenic acid in human erythrocytes infected with the malaria parasite Plasmodium falciparum. doi
  35. (1999). Transport and trafficking in the malariainfected erythrocyte. Parasitol Today doi
  36. (2006). Transport of nucleosides across the Plasmodium falciparum parasite plasma membrane has characteristics of PfENT1. Mol Microbiol doi
  37. (1999). Transport properties of the host cell membrane. Novartis Found Symp
  38. (1979). Vanderberg JP: Synchronization of Plasmodium falciparum erythrocytic stages in culture. doi
  39. (2008). VL: Erythrocytic adenosine monophosphate as an alternative purine source in Plasmodium falciparum. doi
  40. (1988). Woffendin C: Species differences in sensitivity of nucleoside transport in erythrocytes and cultured cells to inhibition by nitrobenzylthioinosine, dipyridamole, dilazep and lidoflazine. Biochim Biophys Acta doi

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