Metal catalyzed lens crystallin oxidation during aging and in diabetes: The role of glutathione

In summary, the data presented in this study suggest metal catalyzed oxidation of lysines occurs in the aging human lens, most likely by the Suyama mechanism involving Cu²⁺, methylglyoxal whereby H₂O ₂ most likely originates from ascorbic acid oxidation. The conversion of allysine to 2-aminoadipic acid does not readily occur in the lens due to the anaerobic environment. Thus, if high levels of 2-AAA are detected, this implicates a functional drop of glutathione and decreased ability to detoxify H₂0₂. Therefore 2-AAA is expected to accumulate during nuclear sclerosis together with the formation of protein-protein and protein-GSH disulfides. The findings strongly implicate dicarbonyl/metal catalyzed oxidation of lysine to allysine, whereby low GSH combined with ascorbate-derived H₂O₂ likely contributes toward 2-AAA formation, since virtually no 2-AAA formed in presence of methylglyoxal instead of ascorbate. An important translational conclusion is that chelating agents might help delay nuclear sclerosis, and that glutathione plays a key role in preventing oxidation of protein carbonyls.