ArticleMolecular pharmacology2013
Pyrimidine salvage in Trypanosoma brucei bloodstream forms and the trypanocidal action of halogenated pyrimidines.
Article in Molecular pharmacology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 59 citations in OpenAlex.
- TargetingFrontiers in microbiology · 2026Review
- SLAM-seq reveals independent contributions of RNA processing and stability to gene expression in African trypanosomes.Nucleic acids research · 2025Article
- Cloning and Characterization ofInternational journal of molecular sciences · 2023Article
- Pyrimidine salvage inFrontiers in cellular and infection microbiology · 2023Article
- TheMolecules (Basel, Switzerland) · 2022Article
- Trypanosoma brucei: Metabolomics for analysis of cellular metabolism and drug discovery.Metabolomics : Official journal of the Metabolomic Society · 2022Review
- Laboratory Selection of Trypanosomatid Pathogens for Drug Resistance.Pharmaceuticals (Basel, Switzerland) · 2022Review
- AInternational journal of molecular sciences · 2022Article
- Comprehensive characterization of purine and pyrimidine transport activities in Trichomonas vaginalis and functional cloning of a trichomonad nucleoside transporter.Molecular microbiology · 2021Article
- Experimental Strategies to Explore Drug Action and Resistance in Kinetoplastid Parasites.Microorganisms · 2020Review
- Investigation of 5'-Norcarbocyclic Nucleoside Analogues as Antiprotozoal and Antibacterial Agents.Molecules (Basel, Switzerland) · 2019Article
- Article
- Fresh insights into the pyrimidine metabolism in the trypanosomatids.Parasites & vectors · 2018Review
- Drug resistance in protozoan parasites.Emerging topics in life sciences · 2017Article
- Pyrimidine metabolism in schistosomes: A comparison with other parasites and the search for potential chemotherapeutic targets.Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology · 2017Review
- Functional and genetic evidence that nucleoside transport is highly conserved in Leishmania species: Implications for pyrimidine-based chemotherapy.International journal for parasitology. Drugs and drug resistance · 2017Article
- 9-(2'-Deoxy-2'-Fluoro-β-d-Arabinofuranosyl) Adenine Is a Potent Antitrypanosomal Adenosine Analogue That Circumvents Transport-Related Drug Resistance.Antimicrobial agents and chemotherapy · 2017Article
- Pyrimidine Salvage Enzymes Are Essential for De Novo Biosynthesis of Deoxypyrimidine Nucleotides in Trypanosoma brucei.PLoS pathogens · 2016Article
- Metabolomics-Based Screening of the Malaria Box Reveals both Novel and Established Mechanisms of Action.Antimicrobial agents and chemotherapy · 2016Article
- Metabolomic Profiling of the Malaria Box Reveals Antimalarial Target Pathways.Antimicrobial agents and chemotherapy · 2016Article
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Authors and funding
7 authors at 4 institutions in 4 countries.
Funding
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.
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