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Research ArticleArticle

Pyrimidine Salvage in Trypanosoma brucei Bloodstream Forms and the Trypanocidal Action of Halogenated Pyrimidines

Juma A. M. Ali, Darren J. Creek, Karl Burgess, Harriet C. Allison, Mark C. Field, Pascal Mäser and Harry P. De Koning
Molecular Pharmacology February 2013, 83 (2) 439-453; DOI: https://doi.org/10.1124/mol.112.082321
Juma A. M. Ali
Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom (J.A.M.A., D.J.C., K.B., H.P.d.K.); Al Jabal Al Gharbi University, Gharyan, Libya (J.A.M.A.); Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia (D.J.C.); Department of Pathology, University of Cambridge, Cambridge, United Kingdom (H.C.A., M.C.F.); and Swiss Tropical and Public Health Institute, University of Basel, Basel, Switzerland (P.M.)
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Darren J. Creek
Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom (J.A.M.A., D.J.C., K.B., H.P.d.K.); Al Jabal Al Gharbi University, Gharyan, Libya (J.A.M.A.); Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia (D.J.C.); Department of Pathology, University of Cambridge, Cambridge, United Kingdom (H.C.A., M.C.F.); and Swiss Tropical and Public Health Institute, University of Basel, Basel, Switzerland (P.M.)
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Karl Burgess
Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom (J.A.M.A., D.J.C., K.B., H.P.d.K.); Al Jabal Al Gharbi University, Gharyan, Libya (J.A.M.A.); Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia (D.J.C.); Department of Pathology, University of Cambridge, Cambridge, United Kingdom (H.C.A., M.C.F.); and Swiss Tropical and Public Health Institute, University of Basel, Basel, Switzerland (P.M.)
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Harriet C. Allison
Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom (J.A.M.A., D.J.C., K.B., H.P.d.K.); Al Jabal Al Gharbi University, Gharyan, Libya (J.A.M.A.); Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia (D.J.C.); Department of Pathology, University of Cambridge, Cambridge, United Kingdom (H.C.A., M.C.F.); and Swiss Tropical and Public Health Institute, University of Basel, Basel, Switzerland (P.M.)
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Mark C. Field
Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom (J.A.M.A., D.J.C., K.B., H.P.d.K.); Al Jabal Al Gharbi University, Gharyan, Libya (J.A.M.A.); Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia (D.J.C.); Department of Pathology, University of Cambridge, Cambridge, United Kingdom (H.C.A., M.C.F.); and Swiss Tropical and Public Health Institute, University of Basel, Basel, Switzerland (P.M.)
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Pascal Mäser
Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom (J.A.M.A., D.J.C., K.B., H.P.d.K.); Al Jabal Al Gharbi University, Gharyan, Libya (J.A.M.A.); Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia (D.J.C.); Department of Pathology, University of Cambridge, Cambridge, United Kingdom (H.C.A., M.C.F.); and Swiss Tropical and Public Health Institute, University of Basel, Basel, Switzerland (P.M.)
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Harry P. De Koning
Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom (J.A.M.A., D.J.C., K.B., H.P.d.K.); Al Jabal Al Gharbi University, Gharyan, Libya (J.A.M.A.); Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia (D.J.C.); Department of Pathology, University of Cambridge, Cambridge, United Kingdom (H.C.A., M.C.F.); and Swiss Tropical and Public Health Institute, University of Basel, Basel, Switzerland (P.M.)
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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.

Footnotes

  • J.A.M.A. was supported by a personal studentship from the Libyan government.

  • dx.doi.org/10.1124/mol.112.082321.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Received September 10, 2012.
  • Accepted November 27, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 83 (2)
Molecular Pharmacology
Vol. 83, Issue 2
1 Feb 2013
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Research ArticleArticle

Pyrimidine Metabolism in Trypanosoma brucei

Juma A. M. Ali, Darren J. Creek, Karl Burgess, Harriet C. Allison, Mark C. Field, Pascal Mäser and Harry P. De Koning
Molecular Pharmacology February 1, 2013, 83 (2) 439-453; DOI: https://doi.org/10.1124/mol.112.082321

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Research ArticleArticle

Pyrimidine Metabolism in Trypanosoma brucei

Juma A. M. Ali, Darren J. Creek, Karl Burgess, Harriet C. Allison, Mark C. Field, Pascal Mäser and Harry P. De Koning
Molecular Pharmacology February 1, 2013, 83 (2) 439-453; DOI: https://doi.org/10.1124/mol.112.082321
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