Interaction of antimony tartrate with the tripeptide glutathione

Publisher Website
Google Scholar
Abstract
The tripeptide glutathione (γ‐l‐Glu‐l‐Cys‐Gly, GSH) is thought to play an important role in the biological processing of antimony drugs. We have studied the complexation of the antileishmanial drug potassium antimony(III) tartrate to GSH in both aqueous solution and intact red blood cells by NMR spectroscopy and electrospray ionization mass spectrometry. The deprotonated thiol group of the cysteine residue is shown to be the only binding site for Sb(III), and a complex with the stoichiometry [Sb(GS)3] is formed. The stability constant for [Sb(GS)3] was determined to be logK25 (I = 0.1 m, 298 K) based on a competition reaction between tartrate and GSH at different pH* values. In spite of being highly thermodynamically stable, the complex is kinetically labile. The rate of exchange of GSH between its free and Sb‐bound form is pH‐dependent, ranging from slow exchange on the1H‐NMR timescale at low pH (2 s−1at pH 3.2) to relatively rapid exchange at biological pH (> 440 s−1). Such facile exchange may be important in the transport of Sb(III) in various biofluids and tissuesin vivo. Our spin–echo1H‐NMR data show that Sb(III) rapidly entered red blood cell walls and was complexed by intracellular glutathione.