ArticleThe Biochemical journal2005
Phenotypic analysis of trypanothione synthetase knockdown in the African trypanosome.
Article in The Biochemical journal, 2005. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed.
- LC-MS Evaluation of the Redox Trypanothione Balance inAntioxidants (Basel, Switzerland) · 2025Article
- Article
- Tackling Sleeping Sickness: Current and Promising Therapeutics and Treatment Strategies.International journal of molecular sciences · 2023Review
- Discovery of a HiddenACS omega · 2023Article
- Drug-like molecules with anti-trypanothione synthetase activity identified by high throughput screening.Journal of enzyme inhibition and medicinal chemistry · 2022Article
- Trypanothione synthetase confers growth, survival advantage and resistance to anti-protozoal drugs in Trypanosoma cruzi.Free radical biology & medicine · 2019Article
- Deciphering the interplay between cysteine synthase and thiol cascade proteins in modulating Amphotericin B resistance and survival of Leishmania donovani under oxidative stress.Redox biology · 2017Article
- In silico, in vitro, X-ray crystallography, and integrated strategies for discovering spermidine synthase inhibitors for Chagas disease.Scientific reports · 2017Article
- In vitro antileishmanial activity of fisetin flavonoid via inhibition of glutathione biosynthesis and arginase activity in Leishmania infantum.Pathogens and global health · 2017Article
- Genetic validation of Trypanosoma brucei glutathione synthetase as an essential enzyme.Eukaryotic cell · 2014Article
- Molecular mechanisms of in vitro betulin-induced apoptosis of Leishmania donovani.The American journal of tropical medicine and hygiene · 2014Article
- The silicon trypanosome: a test case of iterative model extension in systems biology.Advances in microbial physiology · 2014Review
- Stage-dependent expression and up-regulation of trypanothione synthetase in amphotericin B resistant Leishmania donovani.PloS one · 2014Article
- Mathematical modelling of polyamine metabolism in bloodstream-form Trypanosoma brucei: an application to drug target identification.PloS one · 2013Article
- Induction of oxidative stress in Trypanosoma brucei by the antitrypanosomal dihydroquinoline OSU-40.Antimicrobial agents and chemotherapy · 2012Article
- Design, synthesis and biological evaluation of Trypanosoma brucei trypanothione synthetase inhibitors.ChemMedChem · 2012Article
- The crystal structures of the tryparedoxin-tryparedoxin peroxidase couple unveil the structural determinants of Leishmania detoxification pathway.PLoS neglected tropical diseases · 2012Article
- A global comparison of the human and T. brucei degradomes gives insights about possible parasite drug targets.PLoS neglected tropical diseases · 2012Article
- Transgenic biosynthesis of trypanothione protects Escherichia coli from radiation-induced toxicity.Radiation research · 2010Article
- Proteomics of Trypanosoma evansi infection in rodents.PloS one · 2010Article
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Authors and funding
4 authors.
Funding
Abstract
Trypanothione plays a pivotal role in defence against chemical and oxidant stress, thiol redox homoeostasis, ribonucleotide metabolism and drug resistance in parasitic kinetoplastids. In Trypanosoma brucei, trypanothione is synthesized from glutathione and spermidine by a single enzyme, TryS (trypanothione synthetase), with glutathionylspermidine as an intermediate. To examine the physiological roles of trypanothione, tetracycline-inducible RNA interference was used to reduce expression of TRYS. Following induction, TryS protein was reduced >10-fold and growth rate was reduced 2-fold, with concurrent 5-10-fold decreases in glutathionylspermidine and trypanothione and an up to 14-fold increase in free glutathione content. Polyamine levels were not significantly different from non-induced controls, and neither was the intracellular thiol redox potential, indicating that these factors are not responsible for the growth defect. Compensatory changes in other pathway enzymes were associated with prolonged suppression of TryS: an increase in trypanothione reductase and gamma-glutamylcysteine synthetase, and a transient decrease in ornithine decarboxylase. Depleted trypanothione levels were associated with increases in sensitivity to arsenical, antimonial and nitro drugs, implicating trypanothione metabolism in their mode of action. Escape mutants arose after 2 weeks of induction, with all parameters, including growth, returning to normal. Selective inhibitors of TryS are required to fully validate this novel drug target.
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