FEBS Letters
FEBS Letters
5 years ago

Buthionine sulfoximine is a multi-target inhibitor of trypanothione synthesis in Trypanosoma cruzi

José Salud Rodríguez-Zavala, Rafael Moreno-Sánchez, Zabdi González-Chávez, Marlen Mejía-Tlachi, Citlali Vázquez, Aketzalli Silva, Emma Saavedra
Buthionine sulfoximine (BSO) induces decreased GSH and trypanothione [T(SH)2] pools in trypanosomatids, presumably because only gamma-glutamylcysteine synthetase (γECS) is blocked. However, some BSO effects cannot be explained by exclusive γECS inhibition; therefore, its effect on the T(SH)2-metabolism pathway in Trypanosoma cruzi was re-examined. Parasites exposed to BSO did not synthesize T(SH)2 even when supplemented with cysteine or glutathione, suggesting trypanothione synthetase (TryS) inhibition by BSO. Indeed, recombinant γECS and TryS, but not glutathione synthetase, were inhibited by BSO and kinetics and docking analyses on a TcTryS 3D model suggested BSO binding at the glutathione site. Furthermore, parasites overexpressing γECS and TryS showed ~50% decreased activities after BSO treatment. These results indicated that BSO is also an inhibitor of TryS. This article is protected by copyright. All rights reserved.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/1873-3468.12904

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