Bioinorganic chemistry of antimony : interaction of antimonial with biomolecules
Abstract of thesis entitled
BIOINORGANIC CHEMISTRY OF ANTIMONY:
INTERACTION OF ANTIMONIAL WITH
for the degree of Doctor of Philosophy
at The University of Hong Kong
in August 2004
Leishmaniasis remains one of the largest killers in the tropics with approximately 1.5 billion at risk and 20 million cases being reported annually. Several antimony compounds, e.g. antimony (III) tartrate (Tartaemetic? and sodium stibogluconate (Pentosam?, have been used for the treatment of leishmaniasis for decades amongst the human population. Despite the well known anti-parasitic action of both pentavalent and trivalent antimony drugs against leishmaniasis, the actual mechanisms responsible for the action of antimony is not clear.
The interaction between antimony and thiol-containing tripeptide glutathione (y-L-Glu-L-Cys-Gly) was examined and the results showed a strong binding of antimony(III)
at the thiolate group of Cys of glutathione. The strength of binding of antimony to glutathione is pH dependent, with the biological pH (ca. 7) value being the strongest. The interaction, though thermodynamically stable (log K ca. 25 at 298 K) is kinetically labile. In addition, antimony could diffuse through the membranes of red blood cells rapidly, and probably binds with glutathione to form [Sb(GS)3] inside cells. Another key target of the antimony drugs is thought to be trypanothione which is a major low molecular mass thiol inside the parasite, and the anti-leishmanial activity of pentavalent antimony (Sbv) is dependent on its reduction to trivalent species (Sbm) inside parasites. Surprisingly, Sbv can be rapidly reduced to its trivalent state by trypanothione at mildly acidic conditions in contrast to its analogy, the glutathione. The reduced Sbni subsequently binds to trypanothione to form an Sbm-trypanothione complex and the binding is again pH dependent and is the strongest at biological pH. Addition of low molecular monothiol ligands such as glutathione and cysteine to the Sbni-trypanothione complex leads to the formation of a ternary complex and the thiolates from both trypanothione and monothiol bind to the Sbm center. In spite of being thermodynamically stable, the complex is kinetically labile and the free and bound forms of thiolates exchange on the !H NMR time-scale. The formation of the ternary complex is important to the transport of antimony and the antileishmania properties of the drugs.
In contrast to mammalian cells, all protozoan parasites studied to date are unable to synthesize the purine ring de novo. The parasites evolved an unique purine salvage strategy which is critical for its survival. Also the synthesis of all important mannose containing biomolecules is directly or indirectly dependent on the availability of GDP-
mannose. The complexation of Sbv to guanosine 5'-monophosphate (GMP) and guanosine 5-diphospho-D-mannose (GDP-mannose) was characterized by preparative HPLC separation, ESI-MS characterization together with ID and 2D NMR spectroscopy. Sbv was able to form mono- and bis-adducts to GMP or GDP-mannose under physiologically relevant conditions. Kinetic studies showed that mono-adduct was kinetically preferred followed by the bis-adducts. Both complexes were more stable at slightly acidic conditions. Selective interference with the fundamental biochemical difference between parasites and hosts, with paraticular revelance to the nucleotide metabolism may be one of the action mechanism of Sb(V) drugs.
School:The University of Hong Kong
School Location:China - Hong Kong SAR
Source Type:Master's Thesis
Keywords:antimony biomolecules bioinorganic chemistry
Date of Publication:01/01/2005