New biomarkers of Maillard reaction damage to proteins

Abstract

The amount of advanced glycation end-products (AGE) in tissue proteins increases in diabetes mellitus, and the concentration of a subclass of AGEs, known as glycoxidation products, also increases with chronological age in proteins. The rate of accumulation of glycoxidation products is accelerated in diabetes and age-adjusted concentrations of two glycoxidation products, N epsilon-(carboxymethyl)lysine (CML) and pentosidine, correlate with the severity of complication in diabetic patients. Although AGEs and glycoxidation products are implicated in the development of diabetic complications, these compounds are present at only trace concentrations in tissue proteins and account for only a fraction of the chemical modifications in AGE proteins prepared in vitro. The future of the AGE hypothesis depends on the chemical characterization of a significant fraction of the total AGEs in tissue proteins, a quantitative assessment of their effects on protein structure and function, and an assessment of their role as mediators of biological responses. In this manuscript we describe recent work leading to characterization of new AGEs and glycoxidation products. These compounds include: (1) the imidazolone adduct formed by reaction of 3-deoxyglucosone with 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) methyl-glyoxal-lysine dimer, which are imidazolium crosslinks formed by reaction of glyoxal or methylglyoxal with lysine residues in protein. The presence of 3-deoxyglucosone, methylglyoxal and glyoxal in vivo and the formation of the above AGEs in model carbonyl-amine reaction systems suggests that these AGEs are also formed in vivo and contribute to tissue damage resulting from the Maillard reaction.

Immunohistochemical Distribution and Quantitative Biochemical Detection of Advanced Glycation End Products in Fetal to Adult Rats and in Rats with Streptozotocin-Induced Diabetes

“…AGE-specific molecules are classified into two groups on the basis of their chemical structures: fluorescent and cross-linked (fluorescent/cross-linked) and nonfluorescent and noncross-linked (nonfluorescent/noncross-linked) Obayashi et al, 1996). Fluorolink belongs to the former group, CML and CEL to the latter group (Ahmed et al, 1997;Horiuchi et al, 1996;Wells-Knecht et al, 1996). This immunohistochemical investigation revealed that the intensities of immunoreactivity for the anti-AGE monoclonal antibodies varied in the different organs and tissues of adult rats, in agreement with our previous report of results in humans (Ling et al, 1998).…”

Indoxyl Sulfate, Not P-Cresyl Sulfate, is Associated with Advanced Glycation end Products in Patients on Long-Term Hemodialysis

“…Advanced glycation end products (AGEs), pro-inflammatory and pro-oxidative compounds are produced through the non-enzymatic glycation and oxidation of proteins, lipids and nucleic acids [11,12], and these factors accumulate in CKD patients [13,14]. Previous studies showed that AGEs were involved in the pathogenesis of CVD via receptorindependent and receptor-dependent pathways [15,16].…”

Improved Insulin Sensitivity Is Associated With Restricted Intake of Dietary Glycoxidation Products in the db/db Mouse

“…After ingestion, 10% of preformed AGEs are absorbed into the human or rodent circulation (13,14), of which two-thirds are retained in tissues. Among them are tissue-reactive ␣,␤-dicarbonyl-containing intermediate products, such as methylglyoxal (MG), and terminal products, such as ε Ncarboxymethyllysine (CML) (15,16). MG, which has been linked to cellular oxidant stress and apoptosis (17), and CML, which is formed by glycoxidation as well as by lipoxidation (18), have both been identified in vivo and are linked to tissue toxicity (10,16,19).…”