Studies on the structure of glyceraldehyde-modified proteins and the mechanism underlying the pathogenesis of diabetes and ageing

通过N^α-乙酰赖氨酸、N^α-乙酰精氨酸和甘油醛（GLA）的反应，确定MG-H1、甘精胰岛素、精氨酸嘧啶和2-（4-乙酰氨基-4-羧基丁氨基）-5-（5-乙酰氨基-5-羧基戊基）-7-羟基-3，4-二氢吡啶并[3，2-d]嘧啶-5-鎓（P4）为晚期糖基化终产物（AGEs）。此外，通过葡萄糖或果糖的孵育，鉴定了甘油醛、葡糖酮、3-脱氧葡糖醛酮（3-DG）、3-脱氧木酮糖酮、四氢呋喃酮、三氢呋喃酮、3-脱氧四氢呋喃酮、乙二醛和甲基乙二醛。我们发现3-DG通过内质网应激引起小鼠巨噬细胞凋亡，阐明了羰基应激在糖尿病并发症如动脉硬化和衰老发病机制中的意义。GLA、肌酸和N^α-乙酰赖氨酸的反应也产生了甘氨肽和MG-H1的类似物、精氨酸嘧啶和P4。另一方面，我们发现GLA修饰的蛋白质抑制干扰素β刺激的基因表达。

MG-H1, GLAP, argpyrimidine, and 2-(4-acetylamino-4-carboxybutylamino)-5-(5-acetylamino-5-carboxy-pentyl)-7-hydroxy-3, 4-dihydro-pyrido[3,2-d]pyri-midin-5-ium (P4) were identified as AGEs (advanced glycation end products) by the reaction of the N^α-acetyllysine, N^α-acetylarginine, and glyceraldehydes (GLA). Furthermore, glyceraldehyde, glusocone, 3-deoxyglucosone (3-DG), 3-deoxyxylosone, tetrosone, triosone, 3-deoxytetrosone, glyoxal and methylglyoxal were identified by the incubation of glucose or fructose. We found that 3-DG caused apoptosis through the endoplasmic reticulum stress for mouse macrophage cell line, and clarified the significance of the carbonyl stress on the mechanism underlying the pathogenesis of diabetes complication such as arteriosclerosis and ageing. GLAP, and analogs of MG-H1, argpyrimidine, and P4 were also generated from the reaction of GLA, creatine, and N^α-acetyllysine. On the other hand, we revealed that protein modified by GLA suppressed interferon β stimulated gene expression.