ArticleMolecular microbiology2008
Characterization of Trypanosoma brucei dihydroorotate dehydrogenase as a possible drug target; structural, kinetic and RNAi studies.
Article in Molecular microbiology, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 83 citations in OpenAlex.
- Targeting of Leishmania proteins by β-Lapachone derivatives reveals a promising multitarget candidate.Archives of microbiology · 2026Article
- Helicobacter pylori Dihydroorotate Dehydrogenase: a Promising Target for Screening Potential Drug Candidates.Iranian biomedical journal · 2025Article
- Hit-to-Lead Studies of Pyrazinylpiperazines against Visceral Leishmaniasis: Pharmacokinetic Profile andACS pharmacology & translational science · 2025Article
- Exploring the activity of the putative Δ6-desaturase and its role in bloodstream form life-cycle transitions in Trypanosoma brucei.PLoS pathogens · 2025Article
- Unveiling the Antiviral Capabilities of Targeting Human Dihydroorotate Dehydrogenase against SARS-CoV-2.ACS omega · 2024Article
- Characterisation of putative class 1A DHODH-like proteins from Mucorales and dematiaceous mould species.PloS one · 2023Article
- Identification of fungal dihydrouracil-oxidase genes by expression in Saccharomyces cerevisiae.Antonie van Leeuwenhoek · 2022Article
- Class-II dihydroorotate dehydrogenases from three phylogenetically distant fungi support anaerobic pyrimidine biosynthesis.Fungal biology and biotechnology · 2021Article
- Structural and Biochemical Features ofGenes · 2020Article
- The ASCT/SCS cycle fuels mitochondrial ATP and acetate production in Trypanosoma brucei.Biochimica et biophysica acta. Bioenergetics · 2020Article
- Identification of small molecule enzyme inhibitors as broad-spectrum anthelmintics.Scientific reports · 2019Article
- Untargeted LC-MS metabolomic studies of Asteraceae species to discover inhibitors of Leishmania major dihydroorotate dehydrogenase.Metabolomics : Official journal of the Metabolomic Society · 2019Article
- Article
- Crystal structures of FMN-bound and FMN-free forms of dihydroorotate dehydrogenase fromFEBS open bio · 2018Article
- Fresh insights into the pyrimidine metabolism in the trypanosomatids.Parasites & vectors · 2018Review
- Selective Cytotoxicity of Dihydroorotate Dehydrogenase Inhibitors to Human Cancer Cells Under Hypoxia and Nutrient-Deprived Conditions.Frontiers in pharmacology · 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
- Pyrimidine Salvage Enzymes Are Essential for De Novo Biosynthesis of Deoxypyrimidine Nucleotides in Trypanosoma brucei.PLoS pathogens · 2016Article
- The Potential of Secondary Metabolites from Plants as Drugs or Leads against Protozoan Neglected Diseases-Part III: In-Silico Molecular Docking Investigations.Molecules (Basel, Switzerland) · 2016Review
- Evaluation of Antigens for Development of a Serological Test for Human African Trypanosomiasis.PloS one · 2016Article
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 1 country.
Funding
Abstract
Nucleotide biosynthesis pathways have been reported to be essential in some protozoan pathogens. Hence, we evaluated the essentiality of one enzyme in the pyrimidine biosynthetic pathway, dihydroorotate dehydrogenase (DHODH) from the eukaryotic parasite Trypanosoma brucei through gene knockdown studies. RNAi knockdown of DHODH expression in bloodstream form T. brucei did not inhibit growth in normal medium, but profoundly retarded growth in pyrimidine-depleted media or in the presence of the known pyrimidine uptake antagonist 5-fluorouracil (5-FU). These results have significant implications for the development of therapeutics to combat T. brucei infection. Specifically, a combination therapy including a T. brucei-specific DHODH inhibitor plus 5-FU may prove to be an effective therapeutic strategy. We also show that this trypanosomal enzyme is inhibited by known inhibitors of bacterial Class 1A DHODH, in distinction to the sensitivity of DHODH from human and other higher eukaryotes. This selectivity is supported by the crystal structure of the T. brucei enzyme, which is reported here at a resolution of 1.95 A. Additional research, guided by the crystal structure described herein, is needed to identify potent inhibitors of T. brucei DHODH.
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