Pyrimidine salvage in trypanosoma brucei bloodstream forms and the trypanocidal action of halogenated pyrimidines

Ali, J.A.M., Creek, D.J., Burgess, K., Allison, H.C., Field, M.C., Maser, P. and De Koning, H.P. (2013) Pyrimidine salvage in trypanosoma brucei bloodstream forms and the trypanocidal action of halogenated pyrimidines. Molecular Pharmacology, 83(2), pp. 439-453. (doi:10.1124/mol.112.082321) (PMID:23188714)

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Abstract

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 Trypanosoma brucei brucei found that these cells express a high-affinity 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:De Koning, Professor Harry and Creek, Dr Darren and Burgess, Dr Karl
Authors: Ali, J.A.M., Creek, D.J., Burgess, K., Allison, H.C., Field, M.C., Maser, P., and De Koning, H.P.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
College of Medical Veterinary and Life Sciences > School of Life Sciences
Journal Name:Molecular Pharmacology
ISSN:0026-895X
ISSN (Online):1521-0111
Published Online:27 November 2012

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
620261Metabolomic characterisation of clinical biofilms: monitoring of their formation and dispersal on different nanoscale patterned surfaces (ISSF Catalyst)Karl BurgessWellcome Trust (WELLCOME)097821/Z/11/ZIII - PARASITOLOGY