Document Detail


Identification of a nucleoside/nucleobase transporter from Plasmodium falciparum, a novel target for anti-malarial chemotherapy.
MedLine Citation:
PMID:  10861212     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
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:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Biochemical journal     Volume:  349     ISSN:  0264-6021     ISO Abbreviation:  Biochem. J.     Publication Date:  2000 Jul 
Date Detail:
Created Date:  2001-01-26     Completed Date:  2001-07-19     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  2984726R     Medline TA:  Biochem J     Country:  England    
Other Details:
Languages:  eng     Pagination:  67-75     Citation Subset:  IM    
Affiliation:
School of Biochemistry and Molecular Biology, University of Leeds, Leeds LS2 9JT, UK.
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MeSH Terms
Descriptor/Qualifier:
Adenine / 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:
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

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