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Antimicrobial Agents and Chemotherapy, November 2007, p. 3895-3901, Vol. 51, No. 11
0066-4804/07/$08.00+0     doi:10.1128/AAC.00458-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Adenosine Kinase of Trypanosoma brucei and Its Role in Susceptibility to Adenosine Antimetabolites{triangledown} ,{dagger}

Alexandra Lüscher, Pinar Önal,{ddagger} Anne-Marie Schweingruber, and Pascal Mäser*

Institute of Cell Biology, University of Bern, Bern, Switzerland

Received 3 April 2007/ Returned for modification 29 June 2007/ Accepted 4 August 2007

Trypanosoma brucei cannot synthesize purines de novo and relies on purine salvage from its hosts to build nucleic acids. With adenosine being a preferred purine source of bloodstream-form trypanosomes, adenosine kinase (AK; EC 2.7.1.20) is likely to be a key player in purine salvage. Adenosine kinase is also of high pharmacological interest, since for many adenosine antimetabolites, phosphorylation is a prerequisite for activity. Here, we cloned and functionally characterized adenosine kinase from T. brucei (TbAK). TbAK is a tandem gene, expressed in both procyclic- and bloodstream-form trypanosomes, whose product localized to the cytosol of the parasites. The RNA interference-mediated silencing of TbAK suggested that the gene is nonessential under standard growth conditions. Inhibition or downregulation of TbAK rendered the trypanosomes resistant to cordycepin (3'-deoxyadenosine), demonstrating a role for TbAK in the activation of adenosine antimetabolites. The expression of TbAK in Saccharomyces cerevisiae complemented a null mutation in the adenosine kinase gene ado1. The concomitant expression of TbAK with the T. brucei adenosine transporter gene TbAT1 allowed S. cerevisiae ado1 ade2 double mutants to grow on adenosine as the sole purine source and, at the same time, sensitized them to adenosine antimetabolites. The coexpression of TbAK and TbAT1 in S. cerevisiae ado1 ade2 double mutants proved to be a convenient tool for testing nucleoside analogues for uptake and activation by T. brucei adenosine salvage enzymes.

* Corresponding author. Mailing address: Institute of Cell Biology, Baltzerstrasse 4, CH-3012 Bern, Switzerland. Phone: 41 31 631 4673. Fax: 41 31 631 4684. E-mail: pascal.maeser{at}izb.unibe.ch

{triangledown} Published ahead of print on 13 August 2007.

{dagger} Supplemental material for this article may be found at http://aac.asm.org/.

{ddagger} Present address: Biological Sciences and Bioengineering Program, Faculty of Engineering and Natural Sciences, Sabanci University, 34956 Orhanli Tuzla, Istanbul, Turkey.

Antimicrobial Agents and Chemotherapy, November 2007, p. 3895-3901, Vol. 51, No. 11
0066-4804/07/$08.00+0     doi:10.1128/AAC.00458-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Vodnala, M., Fijolek, A., Rofougaran, R., Mosimann, M., Maser, P., Hofer, A. (2008). Adenosine Kinase Mediates High Affinity Adenosine Salvage in Trypanosoma brucei. J. Biol. Chem. 283: 5380-5388 [Abstract] [Full Text]  


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