THE ADVANCED GLYCATION END-PRODUCT, N-(EPSILON)(CARBOXYMETHYL)LYSINE,IS A PRODUCT OF BOTH LIPID-PEROXIDATION AND GLYCOXIDATION REACTIONS

N-epsilon-(Carboxymethyl)lysine (CML) is an advanced glycation end pro duct formed on protein by combined nonenzymatic glycation and oxidatio n (glycoxidation) reactions, We now report that CML is also formed dur ing metal-catalyzed oxidation of polyunsaturated fatty acids in the pr esence of protein. During copper-catalyzed oxidation in vitro, the CML content of low density lipoprotein increased in concert with conjugat ed dienes but was independent of the presence of the Amadori compound, fructoselysine, on the protein, CML was also formed in a time-depende nt manner in RNase incubated under aerobic conditions in phosphate buf fer containing arachidonate or linoleate; only trace amounts of CML we re formed from oleate. After 6 days of incubation the yield of CML in RNase from arachidonate was similar to 0.7 mmol/mol lysine compared wi th only 0.03 mmol/mol lysine for protein incubated under the same cond itions with glucose. Glyoxal, a known precursor of CML, was also forme d during incubation of RNase with arachidonate. These results suggest that lipid peroxidation, as well as glycoxidation, may be an important source of CML in tissue proteins in vivo and that CML may be a genera l marker of oxidative stress and long term damage to protein in aging, atherosclerosis, and diabetes.