Oxidation-Reduction Properties of Methylglyoxal-modified Protein in Relation to Free Radical Generation

Abstract

Glycation reaction (nonenzymatic glycosylation; Maillard reaction), which produces brown fluorescent compounds, is a chance event that may occur when a protein is in solution with a reducing sugar, such as glucose. In this reaction, free amino groups of protein react slowly with the carbonyl groups of reducing sugars to yield Schiff-base intermediates, which undergo Amadori rearrangement to stable ketoamine derivatives (1). These Amadori products subsequently degrade into ␣-dicarbonyl compounds, deoxyglucosones (2). Schiff bases can also be fragmented to glyoxal (3). These compounds are more reactive than the parent sugars with respect to their ability to react with amino groups of proteins. Thus, the ␣-dicarbonyl compounds or ␣-ketoaldehydes are mainly responsible for forming inter-and intramolecular cross-links of proteins, known as advanced glycation end products (AGEs) 1 (1). The AGEs, which are irreversibly formed, accumulate with aging, atherosclerosis, and diabetes mellitus, especially associated with long-lived proteins such as collagens, lens crystallins, and nerve proteins (4 -8).The ␣-dicarbonyl compounds are produced in a variety of ways. Fenton reaction-mediated oxidation of sugars, lipids, and proteins produces various ␣-dicarbonyl compounds. Accordingly, the transition metal ion-catalyzed oxidation of glucose is suggested to be a more important factor in glycation than the formation of the Amadori product of glucose itself (9 -11). The ␣-ketoaldehydes, such as methylglyoxal, are also found as a normal metabolite in mammals and microorganisms. The methylglyoxal is formed by the non-enzymatic or enzymatic elimination of phosphate from triose phosphate and by the oxidation of hydroxyacetone and aminoacetone (12-14). The increased formation of methylglyoxal was observed in hyperglycemia associated with diabetes mellitus (15, 16). In addition, it was shown that methylglyoxal-modified albumin underwent receptor-mediated endocytosis by macrophage, which may suggest the involvement of methylglyoxal in pathophysiology (17). Also, it was suggested that cellular oxidant stress or free radicals are generated by AGEs themselves (18,19) or as a consequence of the AGEs interaction with their receptors (20,21).Several AGEs were identified from the products formed during the reaction of methylglyoxal with model compounds and proteins. These species include N ⑀ -(carboxyethyl)lysine (22), imidazolone compounds (23), and imidazolium cross-link species, methylglyoxal-lysine dimer (24 -26). In addition to these AGEs, several investigations have also shown by electron paramagnetic resonance (EPR) spectroscopy that unidentified protein free radicals were produced during the reaction of methylglyoxal with proteins, such as bovine serum albumin (BSA) and casein (27,28). In our previous report (29), the free radical was assigned to be the radical cation of the cross-linked Schiff base on the basis of the detailed analysis of EPR spectra observed from the reaction mixture containing methylglyoxal and alanine. We also sugges...

Oxidative modification of ferritin induced by methylglyoxal

“…The increased formation of MG was observed in hyperglycemia associated with diabetes mellitus (32,43). It has been reported that MG-mediated protein modifications led to the formation of free radicals (44). We show here that ROS scavengers inhibited the MG-mediated ferritin modification.…”

Inhibitory Effects of Hydroxysafflor Yellow A on the Formation of Advanced Glycation End Products <i>in Vitro</i>

“…It was shown that MGO can readily react with protein residues such as lysine to produce high molecular weight, cross-linked products. 4,23) This could be demonstrated by protein map of MGO-treated BSA under denaturing conditions using SDS-PAGE. As shown in Fig.…”

A hydroxyl radical–like species oxidizes cynomolgus monkey artery wall proteins in early diabetic vascular disease

“…Studies with model systems demonstrate that Schiff base adducts of methylglyoxal (an α-dicarbonyl that increases in diabetes) generate radical cations and superoxide (43,44). These reactions are independent of free metal ions, and they can be executed by protein-bound methylglyoxal, suggesting that this pathway may contribute to oxidative stress in diabetes.…”