Nucleoside uptake in Trypanosoma cruzi: analysis of a mutant resistant to tubercidin.
Nucleoside salvage pathways are vital to the parasitic protozoan Trypanosoma cruzi, and have become important targets in the development of new chemotherapeutic agents against this organism. We produced a mutant T. cruzi clone with a defect in the uptake of the adenosine analogue tubercidin which allowed us to hypothesize that there are at least two distinct nucleoside transport pathways in this parasite. The mutant shows a marked defect in the uptake of tubercidin and thymidine, whereas the uptake of adenosine and inosine are normal. Inhibition and metabolic studies suggest that the defect is related to transport and that there are two transport processes relatively specific for purines and pyrimidines, respectively, although tubercidin is transported via the latter. This is similar to the reported dual nucleoside transport pathways in Leishmania donovani and may be a common system in the Trypanosomatidae. These transport processes are markedly different from those which have been described for mammalian cells and may play an important role in the design of strategies for the chemotherapy of human infection with these pathogenic parasites.
Finley
R W
RW
Laboratory of Parasitic Diseases, National Cancer Institute, Bethesda, MD 20892.
Cooney
D A
DA
Dvorak
J A
JA
D000241:Adenosine / Q000378:metabolism; D000617:Aminoglycosides; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001692:Biological Transport; D003001:Cloning, Molecular; D004351:Drug Resistance; D007288:Inosine / Q000378:metabolism; D009154:Mutation; D009705:Nucleosides / Q000378:metabolism*; D011687:Purines / Q000378:metabolism; D011743:Pyrimidines / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D014372:Tubercidin / Q000378:metabolism / Q000494:pharmacology*; D014529:Uridine / Q000378:metabolism; D014633:Valine / Q000378:metabolism
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D009705:Nucleosides; D011687:Purines; D011743:Pyrimidines; D007288:Inosine; D014633:Valine; D000241:Adenosine; D014372:Tubercidin; D013936:Thymidine; D014529:Uridine