Protein-Thiol Mixed Disulfides and Thioltransferase in the Lens

Abstract

Oxidative stress is considered an important factor in human senile cataract formation, in fact many consider it as the primary mechanism that is responsible for cataracts. Oxidative damage can affect intracellular proteins as well as lens membranes. We have studied oxidative damage to lens proteins that involve the sulfhydryl groups that are most sensitive to oxidative stress. In fact most cataracts are characterized by an increase in protein disulfides (PS SP). Our studies suggest that the synthesis of PSSP is preceded by formation of protein-thiol mixed disulfide between protein and oxidized glutathione (PSSG) or protein and oxidized cysteine (PSSC). A normal lens contains nanomole quantities of PSSG and PSSC, at the level of 2-5% of free glutathione (GSH). However, these compounds can be elevated extensively in human cataractous lenses as well as in oxidative stress-induced cataracts in human and animal lenses. The latter include cataracts induced by hyperbaric oxygen, naphthalene, ultraviolet light, diquat and hydrogen peroxide. Even the Emory mouse cataract, a genetic cataract occurring in aging mice, contains a significant amount of the protein-thiol mixed disulfides. If the oxidant is removed from the environment, the elevated protein-thiol mixed disulfides, in particular PSSG, can spontaneously return to the normal level. This recovery process is age-dependent in the human lens but not in the rat lens. We speculate that this recovery process may be mediated by thioltransferase, a redox regulating enzyme that is known in other tissues to dethiolate protein-thiol mixed disulfides. We have recently found this enzyme in the lens as well as in other ocular tissues. Therefore, we propose that protein-thiol mixed disulfides may play an important role in cataract formation while thioltransferase may be a repair system for the lens.