ArticleMolecular microbiology2009
Dissecting the essentiality of the bifunctional trypanothione synthetase-amidase in Trypanosoma brucei using chemical and genetic methods.
Article in Molecular microbiology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 76 citations in OpenAlex.
- Translesion synthesis and microhomology-mediated end-joining repair in trypanosomatids.PLoS neglected tropical diseases · 2025Review
- Targeting Trypanothione Synthetase and Trypanothione Reductase: Development of Common Inhibitors to Tackle Trypanosomatid Disease.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Targeting Trypanothione Metabolism in Trypanosomatids.Molecules (Basel, Switzerland) · 2024Review
- The indole motif is essential for the antitrypanosomal activity of N5-substituted paullones.PloS one · 2023Article
- Drug-like molecules with anti-trypanothione synthetase activity identified by high throughput screening.Journal of enzyme inhibition and medicinal chemistry · 2022Article
- Diverse Biosynthetic Pathways and Protective Functions against Environmental Stress of Antioxidants in Microalgae.Plants (Basel, Switzerland) · 2021Review
- Multiple unbiased approaches identify oxidosqualene cyclase as the molecular target of a promising anti-leishmanial.Cell chemical biology · 2021Article
- Mechanistic and biological characterisation of novelJournal of enzyme inhibition and medicinal chemistry · 2020Article
- Screening Marine Natural Products for New Drug Leads against Trypanosomatids and Malaria.Marine drugs · 2020Review
- Trypanothione synthetase confers growth, survival advantage and resistance to anti-protozoal drugs in Trypanosoma cruzi.Free radical biology & medicine · 2019Article
- Polyamines in protozoan pathogens.The Journal of biological chemistry · 2018Review
- Discovery and Genetic Validation of Chemotherapeutic Targets for Chagas' Disease.Frontiers in cellular and infection microbiology · 2018Review
- Stress-Induced Protein S-Glutathionylation and S-Trypanothionylation in African Trypanosomes-A Quantitative Redox Proteome and Thiol Analysis.Antioxidants & redox signaling · 2017Article
- Anti-trypanosomatid drug discovery: an ongoing challenge and a continuing need.Nature reviews. Microbiology · 2017Review
- Disclosing the essentiality of ribose-5-phosphate isomerase B in Trypanosomatids.Scientific reports · 2016Article
- Identification of Novel Chemical Scaffolds Inhibiting Trypanothione Synthetase from Pathogenic Trypanosomatids.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
- Genetic validation of Trypanosoma brucei glutathione synthetase as an essential enzyme.Eukaryotic cell · 2014Article
- Biochemical and genetic characterization of Trypanosoma cruzi N-myristoyltransferase.The Biochemical journal · 2014Article
- Drug discovery for neglected diseases: molecular target-based and phenotypic approaches.Journal of medicinal chemistry · 2013Review
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
The bifunctional trypanothione synthetase-amidase (TRYS) comprises two structurally distinct catalytic domains for synthesis and hydrolysis of trypanothione (N(1),N(8)-bis(glutathionyl)spermidine). This unique dithiol plays a pivotal role in thiol-redox homeostasis and in defence against chemical and oxidative stress in trypanosomatids. A tetracycline-dependent conditional double knockout of TRYS (cDKO) was generated in bloodstream Trypanosoma brucei. Culture of cDKO parasites without tetracycline induction resulted in loss of trypanothione and accumulation of glutathione, followed by growth inhibition and cell lysis after 6 days. In the absence of inducer, cDKO cells were unable to infect mice, confirming that this enzyme is essential for virulence in vivo as well as in vitro. To establish whether both enzymatic functions were essential, an amidase-dead mutant cDKO line was generated. In the presence of inducer, this line showed decreased growth in vitro and decreased virulence in vivo, indicating that the amidase function is not absolutely required for viability. The druggability of TRYS was assessed using a potent small molecule inhibitor developed in our laboratory. Growth inhibition correlated in rank order cDKO, single KO, wild-type and overexpressing lines and produced the predicted biochemical phenotype. The synthetase function of TRYS is thus unequivocally validated as a drug target by both chemical and genetic methods.
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