ArticleThe Journal of biological chemistry2012
Genetic dissection of pyrimidine biosynthesis and salvage in Leishmania donovani.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 35 citations in OpenAlex.
- Toxoplasma gondii C2 Domain Protein Deletion Mutant as a Promising Vaccine Against Toxoplasmosis in Mice.Microbial biotechnology · 2025Article
- In silico prediction of the metabolism of Blastocrithidia nonstop, a trypanosomatid with non-canonical genetic code.BMC genomics · 2024Article
- Next-Generation Leishmanization: Revisiting Molecular Targets for Selecting Genetically Engineered Live-AttenuatedMicroorganisms · 2023Review
- Systematic identification of genes encoding cell surface and secreted proteins that are essential for in vitro growth and infection in Leishmania donovani.PLoS pathogens · 2022Article
- Decreased glutamate transport in acivicin resistant Leishmania tarentolae.PLoS neglected tropical diseases · 2021Article
- Vaccinia Virus Vectors Targeting Peptides for MHC Class II Presentation to CD4ImmunoHorizons · 2020Article
- Two Deoxythymidine Triphosphate Synthesis-Related Genes Regulate Obligate Symbiont Density and Reproduction in the WhiteflyFrontiers in physiology · 2020Article
- Structural explanation for the tunable substrate specificity of an E. coli nucleoside hydrolase: insights from molecular dynamics simulations.Journal of computer-aided molecular design · 2018Article
- A Leishmania-specific gene upregulated at the amastigote stage is crucial for parasite survival.Parasitology research · 2018Article
- 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
- 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
- Article
- Leishmania infantum Asparagine Synthetase A Is Dispensable for Parasites Survival and Infectivity.PLoS neglected tropical diseases · 2016Article
- Genetically modified organisms and visceral leishmaniasis.Frontiers in immunology · 2014Review
- Gene amplification and point mutations in pyrimidine metabolic genes in 5-fluorouracil resistant Leishmania infantum.PLoS neglected tropical diseases · 2013Article
- Substrate inhibition of uracil phosphoribosyltransferase by uracil can account for the uracil growth sensitivity of Leishmania donovani pyrimidine auxotrophs.The Journal of biological chemistry · 2013Article
- Pyrimidine biosynthesis is not an essential function for Trypanosoma brucei bloodstream forms.PloS one · 2013Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Protozoan parasites of the Leishmania genus express the metabolic machinery to synthesize pyrimidine nucleotides via both de novo and salvage pathways. To evaluate the relative contributions of pyrimidine biosynthesis and salvage to pyrimidine homeostasis in both life cycle stages of Leishmania donovani, individual mutant lines deficient in either carbamoyl phosphate synthetase (CPS), the first enzyme in pyrimidine biosynthesis, uracil phosphoribosyltransferase (UPRT), a salvage enzyme, or both CPS and UPRT were constructed. The Δcps lesion conferred pyrimidine auxotrophy and a growth requirement for medium supplementation with one of a plethora of pyrimidine nucleosides or nucleobases, although only dihydroorotate or orotate could circumvent the pyrimidine auxotrophy of the Δcps/Δuprt double knockout. The Δuprt null mutant was prototrophic for pyrimidines but could not salvage uracil or any pyrimidine nucleoside. The capability of the Δcps parasites to infect mice was somewhat diminished but still robust, indicating active pyrimidine salvage by the amastigote form of the parasite, but the Δcps/Δuprt mutant was completely attenuated with no persistent parasites detected after a 4-week infection. Complementation of the Δcps/Δuprt clone with either CPS or UPRT restored infectivity. These data establish that an intact pyrimidine biosynthesis pathway is essential for the growth of the promastigote form of L. donovani in culture, that all uracil and pyrimidine nucleoside salvage in the parasite is mediated by UPRT, and that both the biosynthetic and salvage pathways contribute to a robust infection of the mammalian host by the amastigote. These findings impact potential therapeutic design and vaccine strategies for visceral leishmaniasis.
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