Wells-Knecht K J, Brinkmann E, Wells-Knecht M C, Litchfield J E, Ahmed M U, Reddy S, Zyzak D V, Thorpe S R, Baynes J W
Department of Chemistry and Biochemistry, University of South Carolina, Columbia 29208, USA.
Nephrol Dial Transplant. 1996;11 Suppl 5:41-7. doi: 10.1093/ndt/11.supp5.41.
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.
糖尿病患者组织蛋白中的晚期糖基化终产物（AGE）含量会增加，并且一类被称为糖氧化产物的AGEs亚类的浓度，也会随着蛋白质的自然老化而增加。糖尿病会加速糖氧化产物的积累，并且两种糖氧化产物Nε-（羧甲基）赖氨酸（CML）和戊糖苷的年龄校正浓度，与糖尿病患者并发症的严重程度相关。尽管AGEs和糖氧化产物与糖尿病并发症的发生有关，但这些化合物在组织蛋白中仅以痕量浓度存在，并且在体外制备的AGE蛋白的化学修饰中仅占一小部分。AGE假说的未来取决于对组织蛋白中总AGEs的很大一部分进行化学表征，对它们对蛋白质结构和功能的影响进行定量评估，以及评估它们作为生物反应介质的作用。在本手稿中，我们描述了导致鉴定新的AGEs和糖氧化产物的近期工作。这些化合物包括：（1）由3-脱氧葡萄糖酮与蛋白质中的精氨酸残基反应形成的咪唑啉酮加合物；（2）Nε-（羧乙基）赖氨酸，一种由甲基乙二醛与赖氨酸反应形成的CML类似物；（3）乙二醛-赖氨酸二聚体；以及（4）甲基乙二醛-赖氨酸二聚体，它们是由乙二醛或甲基乙二醛与蛋白质中的赖氨酸残基反应形成的咪唑鎓交联物。体内存在3-脱氧葡萄糖酮、甲基乙二醛和乙二醛，以及在模型羰基-胺反应体系中形成上述AGEs，表明这些AGEs也在体内形成，并导致美拉德反应引起的组织损伤。
