AMINOMALONIC ACID AND THE CALCIFICATION OF PROTEIN

氨基丙二酸和蛋白质的钙化

• 批准号: 3354954
• 负责人: TAD H KOCH
• 金额: $ 7.35万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-12-01 至 1989-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3354954
• 关键词: amino group; atherosclerosis; calcification inhibitor; carboxylation; crystallization; free radicals; malonates; pericardium; phagocytes; prosthesis

Aminomalonic acid has been discovered in alkaline hydrolysates of bacterial protein, calcified human arterial proteins, and in calcified prosthetic devices fabricated from bovine pericardium. Based upon preliminary evidence, the formation of Ama residues in structural proteins is postulated to be involved in the pathological calcification of these proteins in diseases such atherosclerosis and in prosthetic devices such as artificial heart heart valves. More specifically the proposal states 1) that Ama residues in structural proteins are formed through the post-translational free radical carboxylation of Gly residues, 2) that Ama residues, most likely in clusters, serve as binding sites for calcium ions and consequently, nucleate calcium phosphate crystallization, 3) that the free radical carboxylations is initiated by radicals from decomposition of lipid hydroperoxides possibly those present in arterial fatty streaks which form prior to calcification or by radicals produced by stimulated phagocytes, and 4) that the calcification of prosthetic devices fabricated from bovine pericardium can be dramatically inhibited by blocking Ama formation through the chemical transformation of selected Gly residues to Ser residues. The specific studies which will be performed are 1) the synthesis of peptide units containing Ama residues which might logically be metal binding sites in protein, 2) the determination of the metal binding properties of these peptides, 3) the determination from model studies of the formation of Ama residues via free radical induced carboxylation of Gly residues of structural protein especially type 1 collagen of bovine percardium utilized to fabricate prosthetic devices, 4) the development of the method of free radical conversion of exposed Gly residues to Ser residues for the inhibition of pathological calcification of prosthetic devices, and 5) establishing that the inhibition is in fact related to the blocking of in vivo Ama formation. An important health related result will be the development of a process for the modification of bovine pericardium which will inhibit the in vivo, pathological calcification of prosthetic devices for human implant.

在细菌的碱性水解液中发现了氨基酸酸 蛋白质，钙化人动脉蛋白，并在钙化的假肢中 用牛心包制造的设备。 基于初步 证据，结构蛋白中AMA残基的形成是 假定参与这些病理钙化 疾病中的蛋白质类动脉粥样硬化和假肢中的蛋白质（例如 人造心脏瓣膜。 更具体地说，提案指出1） 结构蛋白中的AMA残基是通过 胶囊残基的翻译后自由基羧化，2）AMA 残留物（最有可能在簇中）充当钙离子的结合位点 因此，成核磷酸钙结晶，3） 自由基的羧基由自由基的分解引发 脂质氢过氧化物可能是在动脉脂肪条纹中存在的脂质氢过氧化物 在钙化之前或由刺激产生的自由基形式 吞噬细胞和4）假体装置的钙化 可以通过阻塞AMA极大地抑制牛心包 通过选定的Gly残基的化学转化形成 Ser残留物。 将进行的具体研究是1） 含有AMA残基的肽单元的合成，可能是逻辑上的 蛋白质中的金属结合位点，2）金属结合的测定 这些肽的特性，3）从模型研究中确定的 通过自由基诱导的Gly形成AMA残基的形成 结构蛋白的残留物，特别是牛的1型胶原蛋白 使用用于制造假肢设备的心心心态，4） 裸露的Gly残留物向Ser的自由基转化的方法 抑制病理钙化的残留物 设备和5）确定抑制实际上与 阻断体内AMA形成。 重要的健康结果将 开发修饰牛心包的过程 这将抑制体内，病理钙化假体​​的钙化 人类植入物的设备。