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.

在细菌的碱性水解产物中发现了氨基丙二酸 蛋白质、钙化人动脉蛋白以及钙化假体 由牛心包制成的装置。 根据初步 证据表明，结构蛋白中 Ama 残基的形成是 推测与这些组织的病理性钙化有关 动脉粥样硬化等疾病和假体装置中的蛋白质 人造心脏心脏瓣膜。 更具体地说，该提案指出 1) 结构蛋白中的 Ama 残基是通过 甘氨酸残基的翻译后自由基羧化，2) Ama 残基，最有可能呈簇状，充当钙离子的结合位点 因此，有核磷酸钙结晶，3) 自由基羧化是由分解产生的自由基引发的 脂质氢过氧化物可能存在于动脉脂肪条纹中 在钙化之前形成或由受刺激产生的自由基形成 吞噬细胞，4) 所制造的假体装置的钙化 通过阻断 Ama 可以显着抑制牛心包 通过选定的甘氨酸残基的化学转化形成 Ser 残基。 将进行的具体研究是 1) 含有 Ama 残基的肽单元的合成，逻辑上可能是 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) 通过模型研究确定 通过自由基诱导的甘氨酸羧化形成 Ama 残基 结构蛋白尤其是牛1型胶原蛋白的残留物 用于制造假肢装置的心膜，4) 的开发 将暴露的Gly残基自由基转化为Ser的方法 残留物抑制假体病理性钙化 装置，以及 5) 确定抑制实际上与 阻断体内 Ama 的形成。 重要的健康相关结果将 牛心包改造工艺的开发 这将抑制假体的体内病理性钙化 用于人体植入的设备。