ASCORBIC ACID GLYCATION & SENILE CATARACT FORMATION

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There has been considerable interest in the glycation of lens proteins as a causative mechanism of both diabetic and senile cataract. The long half life of the lens proteins predict that glycated molecules should accumulate in the lens, and may play a role in the formation of the high molecular weight protein aggregates seen in aged lenses and cataracts. After 10 years of research there has been little progress on identification and quantitation of glycated products, and no direct evidence for protein crosslinking has been forthcoming. We have been studying glycation of lens proteins by ascorbic acid as opposed to glucose. When ascorbic acid is oxidized to dehydroascorbic acid, a rapid glycation and crosslinking occurs which resembles that seen in cataract. Specific amino acid adducts have been isolated, and several of these are present at relatively high concentrations in the water-insoluble fraction from human lens tissue. We intend to obtain more definitive data in the work outlined here by identifying the degradation products of ascorbic acid and studying the rate of formation of each under the conditions present in the lens. The isolation and identification of 5 different lysine adducts is planned, as well as their identification as modified amino acids in cataract extracts. Several approaches will also be taken in an attempt to identify the nature of the crosslink formed between crystallins. Experiments are also designed to see if ascorbic acid can play a role in the generation of oxygen free radicals, and to estimate whether this is a viable mechanism for additional protein damage in vivo.