Maillard Reactions and Oxidation in Cataractogenesis

白内障发生中的美拉德反应和氧化

• 批准号: 6693345
• 负责人: Ram H Nagaraj
• 金额: $ 30.2万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-01 至 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6693345
• 关键词: aging; aldehyde reductase; carbonyl group; cataract; copper; crystallins; diabetic cataract; enzyme activity; enzyme linked immunosorbent assay; free radical oxygen; glutathione; glycosylation; heavy metals; high performance liquid chromatography; histidine; hyperglycemia; intermolecular interaction; iron; laboratory rat; lens proteins; organ culture; oxidative stress; pathologic process; protein binding; protein degradation; tryptophan

DESCRIPTION (provided by applicant): During aging and cataractogenesis, aldehydes and ketones chemically modify lens proteins through the Maillard reaction. This reaction forms chemically diverse products known as advanced glycation end products, or AGEs. Our previous studies show that alpha-dicarbonyl compounds are the major intermediates of AGEs in the lens. We isolated several AGEs from the human lens that are formed from alpha-dicarbonyls, and developed specific chromatographic and immunochemical methods for their detection. Reactive oxygen species (ROS) are also produced during Maillard reactions. We believe that the Maillard reaction damages lens proteins through the combined effect of ROS and AGEs. We recently made the surprising discovery that early glycation products on cataractous lens proteins can produce short-chain carbohydrates and ROS; these, in turn, form AGEs on non-glycated native lens proteins through metal-ion catalyzed reactions. Now we propose to examine the influence of lens protein-bound transitional metal ions on AGE formation from early glycation products. During Maillard reactions, tryptophan is oxidized; the resulting kynurenines can bind transitional metal ions and generate ROS. ROS, in turn, may catalyze histidine oxidation and AGE formation. First we will identify AGE precursor compounds that arise from early glycation products and study how ROS promote AGE formation from them. Next, we will examine the role of kynurenines in AGE formation. We will examine the ability of lens enzymes and low molecular weight compounds to prevent AGE formation and effect of age and cataractogenesis on their function. Finally, using specific pharmacological inhibitors we will evaluate the role of alpha-dicarbonyls in lens protein damage during cataractogenesis. Our studies will clarify the role of alpha-dicarbonyls in lens protein modifications and establish the importance of our newly discovered pathway of AGE formation in cataractogenesis.

描述（由申请人提供）：在衰老和白内障发生期间， 醛和酮通过美拉德对晶状体蛋白进行化学修饰 反应。该反应形成化学多样化的产品，称为先进的 糖基化终产物，或 AGE。我们之前的研究表明 α-二羰基化合物是晶状体中AGEs的主要中间体。我们 从人类晶状体中分离出几种 AGE，它们是由 α-二羰基，并开发了特定的色谱和免疫化学 其检测方法。还会产生活性氧 (ROS) 在美拉德反应期间。我们相信美拉德反应会损坏镜片 通过 ROS 和 AGE 的联合作用产生蛋白质。我们最近做了 令人惊讶的发现，白内障晶状体蛋白上的早期糖化产物 可产生短链碳水化合物和ROS；这些反过来又形成 AGE 通过金属离子催化反应产生非糖化的天然晶状体蛋白。现在我们 提议检查晶状体蛋白结合的过渡金属离子的影响 早期糖化产物中 AGE 的形成。在美拉德反应期间， 色氨酸被氧化；所得犬尿氨酸可以结合过渡金属 离子并产生ROS。 ROS 反过来可能催化组氨酸氧化和 AGE 形成。首先，我们将识别早期产生的 AGE 前体化合物。 糖化产物并研究 ROS 如何促进它们形成 AGE。接下来，我们 将检查犬尿氨酸在 AGE 形成中的作用。我们将检查 晶状体酶和低分子量化合物预防 AGE 的能力 年龄和白内障发生对其功能的形成和影响。最后， 使用特定的药理学抑制剂，我们将评估其作用 白内障发生过程中晶状体蛋白损伤中的α-二羰基。我们的研究 将阐明α-二羰基在晶状体蛋白修饰中的作用和 确定我们新发现的 AGE 形成途径的重要性 白内障发生。