ArticleThe Journal of biological chemistry2011
Dissecting the metabolic roles of pteridine reductase 1 in Trypanosoma brucei and Leishmania major.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 58 citations in OpenAlex.
- Comparative metabolism of conjugated and unconjugated pterins in Crithidia, Leishmania and African trypanosomes.PLoS neglected tropical diseases · 2025Article
- Antileishmanial natural products as potential inhibitors of theIn silico pharmacology · 2024Article
- Recent Advances in Chemotherapeutics for Leishmaniasis: Importance of the Cellular Biochemistry of the Parasite and Its Molecular Interaction with the Host.Pathogens (Basel, Switzerland) · 2023Review
- Kaurane-Type Diterpenoids as Potential Inhibitors of Dihydrofolate Reductase-Thymidylate Synthase in New WorldAntibiotics (Basel, Switzerland) · 2023Article
- Article
- Multitarget, Selective Compound Design Yields Potent Inhibitors of a Kinetoplastid Pteridine Reductase 1.Journal of medicinal chemistry · 2022Article
- Sesquiterpene Lactones with Dual Inhibitory Activity against theMolecules (Basel, Switzerland) · 2021Article
- Evidence of Pyrimethamine and Cycloguanil Analogues as Dual Inhibitors ofPharmaceuticals (Basel, Switzerland) · 2021Article
- Antileishmanial Evaluation of Bark Methanolic Extract ofACS omega · 2021Article
- A computer-aided approach to identify novel Leishmania major protein disulfide isomerase inhibitors for treatment of leishmaniasis.Journal of computer-aided molecular design · 2021Article
- An overview of biochemically characterized drug targets in metabolic pathways of Leishmania parasite.Parasitology research · 2020Review
- Enzymatic and Mutational Analysis of the PruA Pteridine Reductase Required for Pterin-Dependent Control of Biofilm Formation inJournal of bacteriology · 2020Article
- Future Prospects in the Treatment of Parasitic Diseases: 2-Amino-1,3,4-Thiadiazoles in Leishmaniasis.Molecules (Basel, Switzerland) · 2019Review
- Chemoinformatics Strategies for Leishmaniasis Drug Discovery.Frontiers in pharmacology · 2018Review
- Exploiting the 2-Amino-1,3,4-thiadiazole Scaffold To InhibitACS omega · 2017Article
- Trypanosoma brucei DHFR-TS Revisited: Characterisation of a Bifunctional and Highly Unstable Recombinant Dihydrofolate Reductase-Thymidylate Synthase.PLoS neglected tropical diseases · 2016Article
- 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
- LM14 defined medium enables continuous growth of Trypanosoma cruzi.BMC microbiology · 2014Article
- In-silico analyses of sesquiterpene-related compounds on selected Leishmania enzyme-based targets.Molecules (Basel, Switzerland) · 2014Article
- A member of the Ras oncogene family, RAP1A, mediates antileishmanial activity of monastrol.The Journal of antimicrobial chemotherapy · 2013Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Leishmania parasites are pteridine auxotrophs that use an NADPH-dependent pteridine reductase 1 (PTR1) and NADH-dependent quinonoid dihydropteridine reductase (QDPR) to salvage and maintain intracellular pools of tetrahydrobiopterin (H(4)B). However, the African trypanosome lacks a credible candidate QDPR in its genome despite maintaining apparent QDPR activity. Here we provide evidence that the NADH-dependent activity previously reported by others is an assay artifact. Using an HPLC-based enzyme assay, we demonstrate that there is an NADPH-dependent QDPR activity associated with both TbPTR1 and LmPTR1. The kinetic properties of recombinant PTR1s are reported at physiological pH and ionic strength and compared with LmQDPR. Specificity constants (k(cat)/K(m)) for LmPTR1 are similar with dihydrobiopterin (H(2)B) and quinonoid dihydrobiopterin (qH(2)B) as substrates and about 20-fold lower than LmQDPR with qH(2)B. In contrast, TbPTR1 shows a 10-fold higher k(cat)/K(m) for H(2)B over qH(2)B. Analysis of Trypanosoma brucei isolated from infected rats revealed that H(4)B (430 nM, 98% of total biopterin) was the predominant intracellular pterin, consistent with a dual role in the salvage and regeneration of H(4)B. Gene knock-out experiments confirmed this: PTR1-nulls could only be obtained from lines overexpressing LmQDPR with H(4)B as a medium supplement. These cells grew normally with H(4)B, which spontaneously oxidizes to qH(2)B, but were unable to survive in the absence of pterin or with either biopterin or H(2)B in the medium. These findings establish that PTR1 has an essential and dual role in pterin metabolism in African trypanosomes and underline its potential as a drug target.
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