Reduction of pentavalent antimony by trypanothione and formation of a binary and ternary complex of antimony(III) and trypanothione
Tóm tắt
Several pentavalent antimony compounds have been used for the treatment of leishmaniasis for decades. However, the mechanism of these antimony drugs still remains unclear. One of their targets is thought to be trypanothione, a major low molecular mass thiol inside the parasite. We show that pentavalent antimony (SbV) can be rapidly reduced to its trivalent state by trypanothione at mildly acidic conditions and 310 K (k=4.42 M−1 min−1 at pH 6.4), and that SbIII can be bound to trypanothione to form an SbIII-trypanothione complex. NMR data demonstrate that SbIII binds to trypanothione at the two thiolates of the cysteine residues, and that the binding is pH dependent and is strongest at biological pH with a stability constant logK=23.6 at 298 K (0.1 M NaNO3). The addition of low molecular monothiol ligands such as glutathione and cysteine to the SbIII-trypanothione complex results in the formation of a ternary complex. Thiolates from both trypanothione and monothiol bind to the SbIII center. The formation of the ternary complex is important, as the antileishmanial properties of the drugs are probably due to a complex between of SbIII-trypanothione and enzymes. Although thermodynamically stable, the complex is kinetically labile and the free and bound forms of thiolates exchange on the 1H NMR timescale. Such a facile exchange may be crucial for the transport of SbIII within parasites.
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