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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Pyrimidine salvage in trypanosoma brucei bloodstream forms and the trypanocidal action of halogenated pyrimidines
Molecular Pharmacology, Volume 83, No. 2, Year 2013
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Description
African trypanosomes are capable of both pyrimidine biosynthesis and salvage of preformed pyrimidines from the host. However, uptake of pyrimidines in bloodstream form trypanosomes has not been investigated, making it difficult to judge the relative importance of salvage and synthesis or to design a pyrimidine-based chemotherapy. Detailed characterization of pyrimidine transport activities in bloodstream form Trypano-soma brucei brucei found that these cells express a highaffinity uracil transporter (designated TbU3) that is clearly distinct from the procyclic pyrimidine transporters. This transporter had low affinity for uridine and 2′deoxyuridine and was the sole pyrimidine transporter expressed in these cells. In addition, thymidine was taken up inefficiently through a P1-type nucleoside transporter. Of importance, the anticancer drug 5-fluorouracil was an excellent substrate for TbU3, and several 5-fluoropyrimidine analogs were investigated for uptake and trypanocidal activity; 5F-orotic acid, 5F-2′deoxyuridine displayed activity in the low micromolar range. The metabolism and mode of action of these analogs was determined using metabolomic assessments of T. brucei clonal lines adapted to high levels of these pyrimidine analogs, and of the sensitive parental strains. The analysis showed that 5-fluorouracil is incorporated into a large number of metabolites but likely exerts toxicity through incorporation into RNA. 5F-2′dUrd and 5F-2′dCtd are not incorporated into nucleic acids but act as prodrugs by inhibiting thymidylate synthase as 5F-dUMP. We present the most complete model of pyrimidine salvage in T. brucei to date, supported by genome-wide profiling of the predicted pyrimidine biosynthesis and conversion enzymes. Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics.
Authors & Co-Authors
Ali, Juma A.M.
United Kingdom, Glasgow
University of Glasgow
Libya, Nalut
Al-jabal Al-gharbi University
Creek, Darren J.
United Kingdom, Glasgow
University of Glasgow
Australia, Melbourne
University of Melbourne
Burgess, Karl E.V.
United Kingdom, Glasgow
University of Glasgow
Allison, Harriet C.
United Kingdom, Cambridge
University of Cambridge
Field, Mark C.
United Kingdom, Cambridge
University of Cambridge
Mäser, Pascal
Switzerland, Basel
Universitat Basel
De Koning, Harry P.
United Kingdom, Glasgow
University of Glasgow
Statistics
Citations: 61
Authors: 7
Affiliations: 5
Identifiers
Doi:
10.1124/mol.112.082321
ISSN:
0026895X
e-ISSN:
15210111
Research Areas
Cancer