Trypanosoma brucei: a survey of pyrimidine transport activities.
Purine uptake has been studied in many protozoan parasites in the last few years, and several of the purine transporters have been cloned. In contrast, very little is known about the salvage of preformed pyrimidines by protozoa, and no pyrimidine transporters have been cloned, yet chemotherapy based on pyrimidine nucleobases and nucleosides has been as effective as purine antimetabolites in the treatment of infectious and neoplastic disease. Here, we surveyed the presence of pyrimidine transporters in Trypanosoma brucei brucei. We could not detect any mediated uptake of thymine, thymidine or cytidine, but identified a very high-affinity transporter for cytosine, designated C1, with a K(m) value of 0.048+/-0.009 microM. We also confirmed the presence of the previously reported U1 uracil transporter and found it capable of mediating uridine uptake as well, with a K(m) of 33+/-5 microM. A higher-affinity U2 uridine transporter (K(m)=4.1+/-2.1 microM) was also identified, but efficiency of the C1 and U2-mediated transport was low. Pyrimidine antimetabolites were tested as potential trypanocidal agents and only 5-fluorouracil was found to be effective. This drug was efficiently taken up by bloodstream forms of T. b. brucei.
Gudin
Simon
S
Division of Infection and Immunity, Institute of Biomedical and Life Sciences, University of Glasgow, Biomedical Research Center, Glasgow G12 8TA, UK.
Quashie
Neils B
NB
Candlish
Denise
D
Al-Salabi
Mohammed I
MI
Jarvis
Simon M
SM
Ranford-Cartwright
Lisa C
LC
de Koning
Harry P
HP
D000818:Animals; D000963:Antimetabolites / Q000378:metabolism / Q000494:pharmacology; D001692:Biological Transport; D003562:Cytidine / Q000378:metabolism; D003596:Cytosine / Q000378:metabolism; D005260:Female; D005472:Fluorouracil / Q000378:metabolism / Q000494:pharmacology; D021261:Parasitic Sensitivity Tests; D011743:Pyrimidines / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013936:Thymidine / Q000378:metabolism; D013941:Thymine / Q000378:metabolism; D014344:Trypanocidal Agents / Q000378:metabolism / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000378:metabolism*; D014529:Uridine / Q000378:metabolism
D000963:Antimetabolites; D011743:Pyrimidines; D014344:Trypanocidal Agents; D003562:Cytidine; D003596:Cytosine; D013941:Thymine; D005472:Fluorouracil; D013936:Thymidine; D014529:Uridine