| Identification of a nucleoside/nucleobase transporter from Plasmodium falciparum, a novel target for anti-malarial chemotherapy. | |
MedLine Citation:
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PMID: 10861212 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Plasmodium, the aetiologic agent of malaria, cannot synthesize purines de novo, and hence depends upon salvage from the host. Here we describe the molecular cloning and functional expression in Xenopus oocytes of the first purine transporter to be identified in this parasite. This 422-residue protein, which we designate PfENT1, is predicted to contain 11 membrane-spanning segments and is a distantly related member of the widely distributed eukaryotic protein family the equilibrative nucleoside transporters (ENTs). However, it differs profoundly at the sequence and functional levels from its homologous counterparts in the human host. The parasite protein exhibits a broad substrate specificity for natural nucleosides, but transports the purine nucleoside adenosine with a considerably higher apparent affinity (K(m) 0.32+/-0.05 mM) than the pyrimidine nucleoside uridine (K(m) 3.5+/-1.1 mM). It also efficiently transports nucleobases such as adenine (K(m) 0.32+/-0.10 mM) and hypoxanthine (K(m) 0.41+/-0.1 mM), and anti-viral 3'-deoxynucleoside analogues. Moreover, it is not sensitive to classical inhibitors of mammalian ENTs, including NBMPR [6-[(4-nitrobenzyl)thio]-9-beta-D-ribofuranosylpurine, or nitrobenzylthioinosine] and the coronary vasoactive drugs, dipyridamole, dilazep and draflazine. These unique properties suggest that PfENT1 might be a viable target for the development of novel anti-malarial drugs. |
Authors:
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M D Parker; R J Hyde; S Y Yao; L McRobert; C E Cass; J D Young; G A McConkey; S A Baldwin |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: The Biochemical journal Volume: 349 ISSN: 0264-6021 ISO Abbreviation: Biochem. J. Publication Date: 2000 Jul |
Date Detail:
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Created Date: 2001-01-26 Completed Date: 2001-07-19 Revised Date: 2009-11-18 |
Medline Journal Info:
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Nlm Unique ID: 2984726R Medline TA: Biochem J Country: England |
Other Details:
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Languages: eng Pagination: 67-75 Citation Subset: IM |
Affiliation:
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School of Biochemistry and Molecular Biology, University of Leeds, Leeds LS2 9JT, UK. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adenine
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metabolism Amino Acid Sequence Animals Antimalarials / pharmacology* Biological Transport* Blotting, Southern Carrier Proteins / genetics, metabolism Cations Cell Membrane / metabolism Cloning, Molecular Dilazep / pharmacology Dipyridamole / pharmacology Dose-Response Relationship, Drug Hydrogen-Ion Concentration Kinetics Molecular Sequence Data Nucleobase, Nucleoside, Nucleotide, and Nucleic Acid Transport Proteins* Nucleosides / metabolism* Phylogeny Piperazines / pharmacology Plasmodium falciparum / chemistry* Platelet Aggregation Inhibitors / pharmacology Protein Structure, Secondary Protozoan Proteins* Sequence Homology, Amino Acid Substrate Specificity Thioinosine / analogs & derivatives*, pharmacology Time Factors Uridine / metabolism Vasodilator Agents / pharmacology Xenopus |
| Chemical | |
Reg. No./Substance:
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0/Antimalarials; 0/Carrier Proteins; 0/Cations; 0/ENT1 protein, Plasmodium falciparum; 0/Nucleobase, Nucleoside, Nucleotide, and Nucleic Acid Transport Proteins; 0/Nucleosides; 0/Piperazines; 0/Platelet Aggregation Inhibitors; 0/Protozoan Proteins; 0/Vasodilator Agents; 120770-34-5/draflazine; 35898-87-4/Dilazep; 38048-32-7/4-nitrobenzylthioinosine; 574-25-4/Thioinosine; 58-32-2/Dipyridamole; 58-96-8/Uridine; 73-24-5/Adenine |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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