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Molecular Pharmacology

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Research ArticleArticle

Molecular Interactions Underlying the Unusually High Adenosine Affinity of a Novel Trypanosoma brucei Nucleoside Transporter

Mohammed I. Al-Salabi, Lynsey J. M. Wallace, Alexandra Lüscher, Pascal Mäser, Denise Candlish, Boris Rodenko, Matthew K. Gould, Ishrat Jabeen, Sreekantan N. Ajith and Harry P. de Koning
Molecular Pharmacology March 2007, 71 (3) 921-929; DOI: https://doi.org/10.1124/mol.106.031559
Mohammed I. Al-Salabi
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Lynsey J. M. Wallace
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Alexandra Lüscher
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Pascal Mäser
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Denise Candlish
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Boris Rodenko
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Matthew K. Gould
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Ishrat Jabeen
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Sreekantan N. Ajith
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Harry P. de Koning
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Abstract

Trypanosoma brucei encodes a relatively high number of genes of the equilibrative nucleoside transporter (ENT) family. We report here the cloning and in-depth characterization of one T. brucei brucei ENT member, TbNT9/AT-D. This transporter was expressed in Saccharomyces cerevisiae and displayed a uniquely high affinity for adenosine (Km = 0.068 ± 0.013 μM), as well as broader selectivity for other purine nucleosides in the low micromolar range, but was not inhibited by nucleobases or pyrimidines. This selectivity profile is consistent with the P1 transport activity observed previously in procyclic and long-slender bloodstream T. brucei, apart from the 40-fold higher affinity for adenosine than for inosine. We found that, like the previously investigated P1 activity of long/slender bloodstream trypanosomes, the 3′-hydroxy, 5′-hydroxy, N3, and N7 functional groups contribute to transporter binding. In addition, we show that the 6-position amine group of adenosine, but not the inosine 6-keto group, makes a major contribution to binding (ΔG0 = 12 kJ/mol), explaining the different Km values of the purine nucleosides. We further found that P1 activity in procyclic and long-slender trypanosomes is pharmacologically distinct, and we identified the main gene encoding this activity in procyclic cells as NT10/AT-B. The presence of multiple P1-type nucleoside transport activities in T. brucei brucei facilitates the development of nucleoside-based treatments for African trypanosomiasis and would delay the onset of uptake-related drug resistance to such therapy. We show that both TbNT9/AT-D and NT10/AT-B transport a range of potentially therapeutic nucleoside analogs.

Footnotes

  • The work was partly funded by the Wellcome Trust. M.I.A. was funded through a scholarship from the Libyan government. B.R. was funded by a Talent fellowship from the Netherlands Organization for Scientific Research (Nederlandse Organisatie voor Wetenschappelijk Onderzoek).

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

  • doi:10.1124/mol.106.031559.

  • ABBREVIATIONS: ENT, equilibrative nucleoside transporter; AT, adenosine transporter; RT, reverse transcriptase; ORF, open reading frame; LS, long slender; SS, short stumpy; PC, procyclic; kb, kilobase(s).

  • ↵ Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

    • Received October 8, 2006.
    • Accepted December 18, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 71 (3)
Molecular Pharmacology
Vol. 71, Issue 3
1 Mar 2007
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Research ArticleArticle

Molecular Interactions Underlying the Unusually High Adenosine Affinity of a Novel Trypanosoma brucei Nucleoside Transporter

Mohammed I. Al-Salabi, Lynsey J. M. Wallace, Alexandra Lüscher, Pascal Mäser, Denise Candlish, Boris Rodenko, Matthew K. Gould, Ishrat Jabeen, Sreekantan N. Ajith and Harry P. de Koning
Molecular Pharmacology March 1, 2007, 71 (3) 921-929; DOI: https://doi.org/10.1124/mol.106.031559

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Research ArticleArticle

Molecular Interactions Underlying the Unusually High Adenosine Affinity of a Novel Trypanosoma brucei Nucleoside Transporter

Mohammed I. Al-Salabi, Lynsey J. M. Wallace, Alexandra Lüscher, Pascal Mäser, Denise Candlish, Boris Rodenko, Matthew K. Gould, Ishrat Jabeen, Sreekantan N. Ajith and Harry P. de Koning
Molecular Pharmacology March 1, 2007, 71 (3) 921-929; DOI: https://doi.org/10.1124/mol.106.031559
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