Studies of Zinc(II) and Nickel(II) Complexes of GSH, GSSG and Their Analogs Shed More Light on Their Biological Relevance

Glutathione, Upsilon-Glu-Cys-Gly, is one of the most abundant small molecules in biosphere. Its main form is the reduced monomer (GSH), serving to detoxicate xenobiotics and heavy metals, reduce protein thiols, maintain cellular membranes and deactivate free radicals. Its oxidized dimer (GSSG) controls metal content of metallothionein. The results presented provided a quantitative and structural description of Zn(II)- glutathione complexes, including a novel ternary Zn(II)-GSH-His complex. A solution structure for this complex was obtained using 2D-NMR. The Complexes studied may contribute to both zinc and glutathione physiology. In the case of Ni(ll) complexes an interesting dependence of coordination modes on the ratios of reactants was found. At high GSH excess a Ni(GSH)2 complex is formed, with Ni(ll) bonded through S and N and/or O donor atoms. This complex may exist as a high- or low-spin species. Another goal of the studies presented was to describe the catalytic properties of Ni(II) ions towards GSH oxidation, which appeared to be an important step in nickel carcinogenesis. The pH dependence of oxidation rates allowed to determine the Ni(GSH)(2) complex as the most active among the toxicologically relevant species. Protonation and oxidation of metal-free GSH and its analogues were also studied in detail. The monoprotonated form HL(2-) of GSH is the one most susceptible to oxidation, due to a salt bridge between S(-) and NH(3) (+) groups, which activates the thiol.