REACTION OF ASPIRIN WITH CYSTEINYL RESIDUES OF LENS GAMMA-CRYSTALLINS- A MECHANISM FOR THE PROPOSED ANTICATARACT EFFECT OF ASPIRIN

Incubation of lens crystallins with aspirin inhibits the development o f opacities caused by cyanate. Cyanate-induced opacities are thought t o be due to carbamylation of the lysyl residues which causes a decreas e in the protein charge and subsequent conformational changes that per mit disulfide bonding. Because aspirin can also react with lysyl resid ues, it has been proposed that the aspirin inhibition of cataractogene sis is due to acetylation of the lysyl residues which would block thei r reaction with cyanate. However, acetylation of lysyl residues also l owers the protein charge and would be expected to effect changes in pr otein conformation similar to those caused by carbamylation. Therefore , acetylation of the lysyl residues is not a satisfactory explanation for the inhibitory effect of aspirin on lens opacification. Our invest igations of the reactions of cyanate and aspirin with bovine gamma(II) -crystallins show that the cysteinyl residues are also carbamylated an d acetylated at pH 7.4. At this pH, the carbamylation at the cysteinyl residues is reversible, leading to regeneration of the thiol group an d disulfide bonding. In contrast, the acetylation at cysteinyl residue s is stable at pH 7.4 and can prevent disulfide bonding. This differen ce in stability explains how cyanate promotes, and aspirin inhibits, c ataractogenesis.