Buthionine sulfoximine is a multitarget inhibitor of trypanothione synthesis in Trypanosoma cruzi.

Abstract:

:Buthionine sulfoximine (BSO) induces decreased glutathione (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 GSH, suggesting trypanothione synthetase (TryS) inhibition by BSO. Indeed, recombinant γECS and TryS, but not GSH synthetase, were inhibited by BSO and kinetics and docking analyses on a TcTryS 3D model suggested BSO binding at the GSH 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.

journal_name

FEBS Lett

journal_title

FEBS letters

authors

Vázquez C,Mejia-Tlachi M,González-Chávez Z,Silva A,Rodríguez-Zavala JS,Moreno-Sánchez R,Saavedra E

doi

10.1002/1873-3468.12904

subject

Has Abstract

pub_date

2017-12-01 00:00:00

pages

3881-3894

issue

23

eissn

0014-5793

issn

1873-3468

journal_volume

591

pub_type

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