NEW BIOMARKERS OF MAILLARD REACTION DAMAGE TO PROTEINS

The amount of advanced glycation end-products (AGE) in tissue proteins increases in diabetes mellitus, and the concentration of a subclass o f AGEs, known as glycoxidation products, also increases with chronolog ical age in proteins. The rate of accumulation of glycoxidation produc ts is accelerated in diabetes and age-adjusted concentrations of two g lycoxidation products, N-epsilon-(carboxymethyl)lysine (CML) and pento sidine, correlate with the severity of complication in diabetic patien ts. Although AGEs and glycoxidation products are implicated in the dev elopment of diabetic complications, these compounds are present at onl y trace concentrations in tissue proteins and account for only a fract ion of the chemical modifications in AGE proteins prepared in vitro. T he future of the AGE hypothesis depends on the chemical characterizati on of a significant fraction of the total AGEs in tissue proteins, a q uantitative assessment of their effects on protein structure and funct ion, and an assessment of their role as mediators of biological respon ses. In this manuscript we describe recent work leading to characteriz ation of new AGEs and glycoxidation products. These compounds include: (1) the imidazolone adduct formed by reaction of 3-deoxyglucosone wit h arginine residues in protein; (2) N-epsilon-(carboxyethyl)lysine, an analogue of CML formed on reaction of methylglyoxal with lysine; (3) glyoxal-lysine dimer; and (4) methylglyoxal-lysine dimer, which are im idazolium crosslinks formed by reaction of glyoxal or methylglyoxal wi th lysine residues in protein. The presence of 3-deoxyglucosone, methy lglyoxal and glyoxal in vivo and the formation of the above AGEs in mo del carbonyl-amine reaction systems suggests that these AGEs are also formed in vivo and contribute to tissue damage resulting from the Mail lard reaction.