ArticlePLoS pathogens2016
Pyrimidine Salvage Enzymes Are Essential for De Novo Biosynthesis of Deoxypyrimidine Nucleotides in Trypanosoma brucei.
Article in PLoS pathogens, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 34 citations in OpenAlex.
- Targeting Kinetoplastid Parasites with ProTide Prodrugs: A Proof-of-Concept Study.ChemMedChem · 2026Article
- A cytidine deaminase-like protein modulates pyrimidine nucleotide homeostasis in Trypanosoma brucei.Scientific reports · 2025Article
- Genome-wide screens connect HD82 loss-of-function to purine analog resistance in African trypanosomes.mSphere · 2024Article
- A Facile Fluorometric Assay of Orotate Phosphoribosyltransferase Activity Using a Selective Fluorogenic Reaction for Orotic Acid.Sensors (Basel, Switzerland) · 2023Article
- Structure of the catalytically active APOBEC3G bound to a DNA oligonucleotide inhibitor reveals tetrahedral geometry of the transition state.Nature communications · 2022Article
- Sex-specific transcriptome differences in a middle-aged frailty cohort.BMC geriatrics · 2022Article
- Decreased glutamate transport in acivicin resistant Leishmania tarentolae.PLoS neglected tropical diseases · 2021Article
- Enhanced nucleotide analysis enables the quantification of deoxynucleotides in plants and algae revealing connections between nucleoside and deoxynucleoside metabolism.The Plant cell · 2021Article
- An Antiparasitic Compound from the Medicines for Malaria Venture Pathogen Box PromotesACS infectious diseases · 2020Article
- The Emerging Role of Cytidine Deaminase in Human Diseases: A New Opportunity for Therapy?Molecular therapy : the journal of the American Society of Gene Therapy · 2020Review
- Two Deoxythymidine Triphosphate Synthesis-Related Genes Regulate Obligate Symbiont Density and Reproduction in the WhiteflyFrontiers in physiology · 2020Article
- Article
- Alpha-Herpesvirus Thymidine Kinase Genes Mediate Viral Virulence and Are Potential Therapeutic Targets.Frontiers in microbiology · 2019Review
- Screening of the Pathogen Box reveals new starting points for anti-trypanosomal drug discovery.MedChemComm · 2018Article
- Polyamines in protozoan pathogens.The Journal of biological chemistry · 2018Review
- A dual regulatory circuit consisting of S-adenosylmethionine decarboxylase protein and its reaction product controls expression of the paralogous activator prozyme in Trypanosoma brucei.PLoS pathogens · 2018Article
- Fresh insights into the pyrimidine metabolism in the trypanosomatids.Parasites & vectors · 2018Review
- SiSTL2 Is Required for Cell Cycle, Leaf Organ Development, Chloroplast Biogenesis, and Has Effects on CFrontiers in plant science · 2018Article
- 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
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
The human pathogenic parasite Trypanosoma brucei possess both de novo and salvage routes for the biosynthesis of pyrimidine nucleotides. Consequently, they do not require salvageable pyrimidines for growth. Thymidine kinase (TK) catalyzes the formation of dTMP and dUMP and is one of several salvage enzymes that appear redundant to the de novo pathway. Surprisingly, we show through analysis of TK conditional null and RNAi cells that TK is essential for growth and for infectivity in a mouse model, and that a catalytically active enzyme is required for its function. Unlike humans, T. brucei and all other kinetoplastids lack dCMP deaminase (DCTD), which provides an alternative route to dUMP formation. Ectopic expression of human DCTD resulted in full rescue of the RNAi growth phenotype and allowed for selection of viable TK null cells. Metabolite profiling by LC-MS/MS revealed a buildup of deoxypyrimidine nucleosides in TK depleted cells. Knockout of cytidine deaminase (CDA), which converts deoxycytidine to deoxyuridine led to thymidine/deoxyuridine auxotrophy. These unexpected results suggested that T. brucei encodes an unidentified 5'-nucleotidase that converts deoxypyrimidine nucleotides to their corresponding nucleosides, leading to their dead-end buildup in TK depleted cells at the expense of dTTP pools. Bioinformatics analysis identified several potential candidate genes that could encode 5'-nucleotidase activity including an HD-domain protein that we show catalyzes dephosphorylation of deoxyribonucleotide 5'-monophosphates. We conclude that TK is essential for synthesis of thymine nucleotides regardless of whether the nucleoside precursors originate from the de novo pathway or through salvage. Reliance on TK in the absence of DCTD may be a shared vulnerability among trypanosomatids and may provide a unique opportunity to selectively target a diverse group of pathogenic single-celled eukaryotes with a single drug.
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