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Nucleoside uptake in Trypanosoma cruzi: analysis of a mutant resistant to tubercidin
R W Finley1, D A Cooney, J A Dvorak
1Laboratory of Parasitic Diseases, National Cancer Institute, Bethesda, MD 20892.
Abstract:
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.
Insights
This study reveals two distinct nucleoside transport pathways in Trypanosoma cruzi, crucial for developing new antiparasitic drugs. Understanding these pathways aids in designing targeted chemotherapy for Chagas disease.
Area of Science:
- Parasitology
- Molecular Biology
- Drug Discovery
Background:
- Nucleoside salvage pathways are essential for parasitic protozoa like Trypanosoma cruzi.
- These pathways are critical targets for developing novel chemotherapeutic agents against parasitic infections.
Purpose of the Study:
- To investigate the nucleoside transport mechanisms in Trypanosoma cruzi.
- To identify distinct nucleoside transport pathways and their substrate specificities.
Main Methods:
- Generation of a Trypanosoma cruzi mutant with impaired tubercidin uptake.
- Comparative analysis of nucleoside uptake in wild-type and mutant parasites.
- Inhibition and metabolic studies to elucidate transport mechanisms.
Main Results:
- The T. cruzi mutant exhibited significantly reduced uptake of tubercidin and thymidine.
- Uptake of adenosine and inosine remained unaffected in the mutant.
- Evidence suggests two distinct transport systems, one for purines and one for pyrimidines, with tubercidin utilizing the latter.
Conclusions:
- Trypanosoma cruzi possesses at least two nucleoside transport pathways with relative specificity for purines and pyrimidines.
- These pathways differ from mammalian nucleoside transporters, offering potential for selective chemotherapy.
- Findings support a common transport system within Trypanosomatidae, relevant for treating infections caused by these parasites.