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Buthionine sulfoximine is a multitarget inhibitor of trypanothione synthesis in Trypanosoma cruzi
Author(s) -
Vázquez Citlali,
MejiaTlachi Marlen,
GonzálezChávez Zabdi,
Silva Aketzalli,
RodríguezZavala José Salud,
MorenoSánchez Rafael,
Saavedra Emma
Publication year - 2017
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1002/1873-3468.12904
Subject(s) - buthionine sulfoximine , glutathione , trypanosoma cruzi , cysteine , biochemistry , chemistry , metabolism , biology , recombinant dna , enzyme , gene , parasite hosting , world wide web , computer science
Buthionine sulfoximine ( BSO ) induces decreased glutathione (GSH) and trypanothione [T( SH ) 2 ] pools in trypanosomatids, presumably because only gamma‐glutamylcysteine synthetase (γ ECS ) is blocked. However, some BSO effects cannot be explained by exclusive γ ECS 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 GSH, suggesting trypanothione synthetase (TryS) inhibition by BSO . Indeed, recombinant γ ECS and TryS, but not GSH synthetase, were inhibited by BSO and kinetics and docking analyses on a Tc TryS 3D model suggested BSO binding at the GSH site. Furthermore, parasites overexpressing γ ECS and TryS showed ~ 50% decreased activities after BSO treatment. These results indicated that BSO is also an inhibitor of TryS.