Redox-implications associated with the formation of complexes between copper ions and reduced or oxidized glutathione

Binding of copper by reduced glutathione (GSH) is generally seen as a mechanism to lower, if not abolish, the otherwise high electrophilicity and redox activity of its free ions. In recent years, however, this concept has been contradicted by new evidence revealing that, rather than stabilizing free copper ions, its binding to GSH leads to the formation of a Cu(I)-[GSH]2 complex capable of reducing molecular oxygen into superoxide. It is now understood that, under conditions leading to the removal of such radicals, the Cu(I)-[GSH]2 complex is readily oxidized into Cu(II)-GSSG. Interestingly, in the presence of a GSH excess, the latter complex is able to regenerate the superoxide-generating capacity of the complex it originated from, opening the possibility that a GSH-dependent interplay exists between the reduced and the oxidized glutathione forms of these copper-complexes. Furthermore, recent evidence obtained from experiments conducted in non-cellular systems and intact mitochondria indicates that the Cu(II)-GSSG complex is also able to function in a catalytic manner as an efficient superoxide dismutating- and catalase-like molecule. Here we review and discuss the most relevant chemical and biological evidence on the formation of the Cu(I)-[GSH]2 and Cu(II)-GSSG complexes and on the potential redox implications associated with their intracellular occurrence.