ArticleMolecular microbiology2013
Trypanosoma brucei (UMP synthase null mutants) are avirulent in mice, but recover virulence upon prolonged culture in vitro while retaining pyrimidine auxotrophy.
Article in Molecular microbiology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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12 citing papers in PubMed, 23 citations in OpenAlex.
- SLAM-seq reveals independent contributions of RNA processing and stability to gene expression in African trypanosomes.Nucleic acids research · 2025Article
- A Facile Fluorometric Assay of Orotate Phosphoribosyltransferase Activity Using a Selective Fluorogenic Reaction for Orotic Acid.Sensors (Basel, Switzerland) · 2023Article
- 4E Interacting Protein as a Potential Novel Drug Target for Nucleoside Analogues inMicroorganisms · 2021Article
- Roles of the Pumilio domain protein PUF3 inParasitology · 2020Article
- Fresh insights into the pyrimidine metabolism in the trypanosomatids.Parasites & vectors · 2018Review
- 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
- The Role of Folate Transport in Antifolate Drug Action in Trypanosoma brucei.The Journal of biological chemistry · 2016Article
- Pyrimidine Salvage Enzymes Are Essential for De Novo Biosynthesis of Deoxypyrimidine Nucleotides in Trypanosoma brucei.PLoS pathogens · 2016Article
- Article
- Ribose 5-phosphate isomerase B knockdown compromises Trypanosoma brucei bloodstream form infectivity.PLoS neglected tropical diseases · 2015Article
- Homoserine and quorum-sensing acyl homoserine lactones as alternative sources of threonine: a potential role for homoserine kinase in insect-stage Trypanosoma brucei.Molecular microbiology · 2015Article
- The role of the de novo pyrimidine biosynthetic pathway in Cryptococcus neoformans high temperature growth and virulence.Fungal genetics and biology : FG & B · 2014Article
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5 authors at 1 institution in 1 country.
Funding
Abstract
African trypanosomes are capable of both de novo synthesis and salvage of pyrimidines. The last two steps in de novo synthesis are catalysed by UMP synthase (UMPS) - a bifunctional enzyme comprising orotate phosphoribosyl transferase (OPRT) and orotidine monophosphate decarboxylase (OMPDC). To investigate the essentiality of pyrimidine biosynthesis in Trypanosoma brucei, we generated a umps double knockout (DKO) line by gene replacement. The DKO was unable to grow in pyrimidine-depleted medium in vitro, unless supplemented with uracil, uridine, deoxyuridine or UMP. DKO parasites were completely resistant to 5-fluoroorotate and hypersensitive to 5-fluorouracil, consistent with loss of UMPS, but remained sensitive to pyrazofurin indicating that, unlike mammalian cells, the primary target of pyrazofurin is not OMPDC. The null mutant was unable to infect mice indicating that salvage of host pyrimidines is insufficient to support growth. However, following prolonged culture in vitro, parasites regained virulence in mice despite retaining pyrimidine auxotrophy. Unlike the wild-type, both pyrimidine auxotrophs secreted substantial quantities of orotate, significantly higher in the virulent DKO line. We propose that this may be responsible for the recovery of virulence in mice, due to host metabolism converting orotate to uridine, thereby bypassing the loss of UMPS in the parasite.
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