Glycation and Autoxidation of Proteins in Aging and Diabetes

Abstract

Glycation (nonenzymatic glycosylation) of protein is the first step in a complex series of reactions that lead to the gradual browning, cross-linking, and denaturation of proteins by glucose. These reactions are known collectively as the Maillard reaction (17,25,39), in honor of Louis Camille Maillard for his work during the early part of this century, or the browning reaction because of the characteristic brown and fluorescent products formed during the reaction. In food chemistry the brown, soluble products formed during the later stages of the Maillard reaction are known as pre-melanoidins, and the final, insoluble products as melanoidins (17,25,39). In living systems the brown and fluorescent products that accumulate in long-lived proteins are more commonly referred to as advanced glycosylation end products, or AGE-products (8,39). Only a few melanoidins or AGE-products have been structurally characterized; however, it has been apparent for decades that the Maillard reaction is stimulated by oxygen and catalysts of oxidation reactions, such as iron and copper ions, and inhibited by reducing agents, such as bisulfite and thiol compounds (17,25,33). This chapter focuses on the significance of oxidation reactions and their role in mediating the chemical damage caused by glycation and Maillard reactions in vivo. It begins with a discussion of the nature of oxidation and autoxidation reactions, then describes several products of oxidation of glycated proteins that have been identified in vivo, and concludes with a summary of current information regarding the accumulation of these products in tissue proteins with age and in diabetes. Evidence regarding the role of autoxidative glycosylation of protein and the role of Maillard reaction products as catalysts of oxidation of adjacent molecules is also examined. Although glucose is the primary focus of the discussion, the biological significance of autoxidative modification of protein by ascorbate is also considered. We try to present a balance between knowledge and hypothesis, and to point out directions for future research. Among the new ideas to be developed is the proposal that oxidation may be the “fixative” that renders permanent the chemical modification of proteins initiated by glycation. Indeed, the only nonenzymatically formed, carbohydrate-derived products that are known to accumulate in tissue proteins with age, and at an accelerated rate in diabetes, are products of both glycation and oxidation reactions. Thus, the interplay between glycation and oxidation—i.e. “glycoxidation” of protein—may be more important than either glycation or oxidation alone. As will become clear, glycoxidation products constitute a unique group of AGE-products that are biomarkers of chemical damage to protein in aging and diabetes.