During aging and cataractogenesis, aldehydes and ketones chemically modify lens proteins through the Maillard reaction. This reaction forms chemically diverse products known as advanced glycation end products, or AGEs. Our previous studies show that alpha-dicarbonyl compounds are the major intermediates of AGEs in the lens. We isolated several AGEs from the human lens that are formed from alpha-dicarbonyls, and developed specific chromatographic and immunochemical methods for their detection. Reactive oxygen species (ROS) are also produced during Maillard reactions. We believe that the Maillard reaction damages lens proteins through the combined effect of ROS and AGEs. We recently made the surprising discovery that early glycation products on cataractous lens proteins can produce short-chain carbohydrates and ROS; these, in turn, form AGEs on non-glycated native lens proteins through metal-ion catalyzed reactions. Now we propose to examine the influence of lens protein-bound transitional metal ions on AGE formation from early glycation products. During Maillard reactions, tryptophan is oxidized; the resulting kynurenines can bind transitional metal ions and generate ROS. ROS, in turn, may catalyze histidine oxidation and AGE formation. First we will identify AGE precursor compounds that arise from early glycation products and study how ROS promote AGE formation from them. Next, we will examine the role of kynurenines in AGE formation. We will examine the ability of lens enzymes and low molecular weight compounds to prevent AGE formation and effect of age and cataractogenesis on their function. Finally, using specific pharmacological inhibitors we will evaluate the role of alpha-dicarbonyls in lens protein damage during cataractogenesis. Our studies will clarify the role of alpha-dicarbonyls in lens protein modifications and establish the importance of our newly discovered pathway of AGE formation in cataractogenesis.
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