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Originally published In Press as doi:10.1074/jbc.M202835200 on May 9, 2002

J. Biol. Chem., Vol. 277, Issue 29, 26149-26156, July 19, 2002
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Different Substrate Recognition Motifs of Human and Trypanosome Nucleobase Transporters
SELECTIVE UPTAKE OF PURINE ANTIMETABOLITES*

Lynsey J. M. Wallace, Denise Candlish, and Harry P. De KoningDagger

From the Institute of Biomedical and Life Sciences, Division of Infection and Immunity, Joseph Black Building, University of Glasgow, Glasgow G12 8QQ, Scotland, United Kingdom

The therapeutic index of antimetabolites such as purine analogues is in large part determined by the extent to which it is selectively accumulated by the target cell. In the current study we have compared the transport of purine nucleobase analogues by the H2 transporter of bloodstream form Trypanosoma brucei brucei and the equilibrative nucleobase transporter of human erythrocytes. The H2 transporter forms hydrogen bonds with hypoxanthine at positions N3, N7, N(1)H, and N(9)H of the purine ring, with apparent Delta G0 of 7.7-12.6 kJ/mol. The transporter also appears to H-bond with the amine group of adenine. The human transporter forms hydrogen bonds that form to (6)NH2 and N1 of adenine. An H-bond is also formed with N3 and the 6-keto and amine groups of guanine but not with the protonated N1, thus explaining the low affinity for hypoxanthine. N7 and N9 do not directly interact with the human transporter in the form of H-bonds, and it is proposed that pi -pi stacking interactions contribute significantly to permeant binding. The potential for selective uptake of antimetabolites by the parasite transporter was demonstrated.

* This work was supported by the Wellcome Trust.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed. Tel./Fax: 44-141-330-3753; E-mail: H.de-koning@bio.gla.ac.uk.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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