Methylglyoxal inhibits glycation-mediated loss in chaperone function and synthesis of pentosidine in α-crystallin

Abstract

α-Crystallin is a major protein in the eye lens and it functions as a molecular chaperone by preventing aggregation of mildly denatured proteins. Glycation, the reaction of sugars and ascorbate with proteins, causes covalent cross-linking and reduces the chaperone function of α-crystallin. We demonstrated that methylglyoxal (MGO), a metabolic α-dicarbonyl compound, modifies arginine residues in α-crystallin and enhances its chaperone function. We wanted to determine whether modification by MGO could protect α-crystallin from glycation-mediated cross-linking and loss of chaperone function. Our results show that MGO-modification of isolated bovine lens α-crystallin inhibits formation of pentosidine, a glycation-derived protein crosslink. Proteins in organ cultured rat lenses were similarly protected from pentosidine formation. Glycation by sugars and ascorbate resulted in almost complete loss of chaperone function of α-crystallin. Surprisingly, addition of MGO during or before glycation not only inhibited the loss of chaperone function, but it actually enhanced the chaperone function of α-crystallin. Together, these data suggest that in the aging lens, MGO inhibits glycation-mediated pentosidine synthesis and the loss of chaperone function of α-crystallin.