Identification and characterisation of high affinity nucleoside and nucleobase transporters in Toxoplasma gondii

De Koning, H. , Al-Salabi, M., Cohen, A., Coombs, G. and Wastling, J. (2003) Identification and characterisation of high affinity nucleoside and nucleobase transporters in Toxoplasma gondii. International Journal for Parasitology, 33(8), pp. 821-831. (doi:10.1016/S0020-7519(03)00091-2)

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Abstract

The protozoan parasite Toxoplasma gondii depends upon salvaging the purines that it requires. We have re-analysed purine transport in T. gondii and identified novel nucleoside and nucleobase transporters. The latter transports hypoxanthine (TgNBT1; ) and is inhibited by guanine and xanthine: it is the first high affinity nucleobase transporter to be identified in an apicomplexan parasite. The previously reported nucleoside transporter, TgAT1, is low affinity with Km values of 105 and 134 μM for adenosine and inosine, respectively. We have now identified a second nucleoside transporter, TgAT2, which is high affinity and inhibited by adenosine, inosine, guanosine, uridine and thymidine (Km values 0.28–1.5 μM) as well as cytidine (). TgAT2 also recognises several nucleoside analogues with therapeutic potential. We have investigated the basis for the broad specificity of TgAT2 and found that hydrogen bonds are formed with the 3′ and 5′ hydroxyl groups and that the base groups are bound through H-bonds with either N3 of the purine ring or N(3)H of the pyrimidine ring, and most probably π–π-stacking as well. The identification of these high affinity purine nucleobase and nucleoside transporters reconciles for the first time the low abundance of free nucleosides and nucleobases in the intracellular environment with the efficient purine salvage carried out by T. gondii.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:De Koning, Professor Harry and Coombs, Professor Graham
Authors: De Koning, H., Al-Salabi, M., Cohen, A., Coombs, G., and Wastling, J.
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:International Journal for Parasitology
Publisher:Elsevier
ISSN:0020-7519
ISSN (Online):1879-0135
Published Online:10 May 2003

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