ArticleThe FEBS journal2008
ATP-dependent ligases in trypanothione biosynthesis--kinetics of catalysis and inhibition by phosphinic acid pseudopeptides.
Article in The FEBS journal, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
10 citing papers in PubMed, 29 citations in OpenAlex.
- Chemoselective bicyclobutane-based mass spectrometric detection of biological thiols uncovers human and bacterial metabolites.Chemical science · 2023Article
- Drug-like molecules with anti-trypanothione synthetase activity identified by high throughput screening.Journal of enzyme inhibition and medicinal chemistry · 2022Article
- Ensemble learning application to discover new trypanothione synthetase inhibitors.Molecular diversity · 2021Article
- Mechanistic and biological characterisation of novelJournal of enzyme inhibition and medicinal chemistry · 2020Article
- Evolution of metabolic capabilities and molecular features of diplonemids, kinetoplastids, and euglenids.BMC biology · 2020Article
- Identification of Novel Chemical Scaffolds Inhibiting Trypanothione Synthetase from Pathogenic Trypanosomatids.PLoS neglected tropical diseases · 2016Article
- Dissecting the catalytic mechanism of Trypanosoma brucei trypanothione synthetase by kinetic analysis and computational modeling.The Journal of biological chemistry · 2013Article
- Molecular dynamics reveal binding mode of glutathionylspermidine by trypanothione synthetase.PloS one · 2013Article
- Design, synthesis and biological evaluation of Trypanosoma brucei trypanothione synthetase inhibitors.ChemMedChem · 2012Article
- Chemical validation of trypanothione synthetase: a potential drug target for human trypanosomiasis.The Journal of biological chemistry · 2009Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
Glutathionylspermidine is an intermediate formed in the biosynthesis of trypanothione, an essential metabolite in defence against chemical and oxidative stress in the Kinetoplastida. The kinetic mechanism for glutathionylspermidine synthetase (EC 6.3.1.8) from Crithidia fasciculata (CfGspS) obeys a rapid equilibrium random ter-ter model with kinetic constants K(GSH) = 609 microM, K(Spd) = 157 microM and K(ATP) = 215 microM. Phosphonate and phosphinate analogues of glutathionylspermidine, previously shown to be potent inhibitors of GspS from Escherichia coli, are equally potent against CfGspS. The tetrahedral phosphonate acts as a simple ground state analogue of glutathione (GSH) (K(i) approximately 156 microM), whereas the phosphinate behaves as a stable mimic of the postulated unstable tetrahedral intermediate. Kinetic studies showed that the phosphinate behaves as a slow-binding bisubstrate inhibitor [competitive with respect to GSH and spermidine (Spd)] with rate constants k(3) (on rate) = 6.98 x 10(4) M(-1) x s(-1) and k(4) (off rate) = 1.3 x 10(-3) s(-1), providing a dissociation constant K(i) = 18.6 nM. The phosphinate analogue also inhibited recombinant trypanothione synthetase (EC 6.3.1.9) from C. fasciculata, Leishmania major, Trypanosoma cruzi and Trypanosoma brucei with K(i)(app) values 20-40-fold greater than that of CfGspS. This phosphinate analogue remains the most potent enzyme inhibitor identified to date, and represents a good starting point for drug discovery for trypanosomiasis and leishmaniasis.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.