AMINOMALONIC ACID AND THE CALCIFICATION OF PROTEIN

氨基丙二酸存在于细菌的碱性水解物中， 蛋白质，钙化的人动脉蛋白质，以及钙化的假体 由牛心包制成的器械。 根据初步 证据表明，结构蛋白中Ama残基的形成是 假设参与这些组织的病理性钙化， 蛋白质在疾病如动脉粥样硬化和假体装置， 人工心脏瓣膜 更具体地说，提案指出：（1） 结构蛋白中的Ama残基是通过 Gly残基的翻译后自由基羧化，2）Ama 残基，最有可能在集群中，作为钙离子的结合位点， 从而使磷酸钙结晶成核，3） 自由基羧化反应是由分解的自由基引发的。 脂质过氧化氢可能存在于动脉脂肪条纹中， 在钙化之前形成或由刺激产生的自由基形成 吞噬细胞，以及4）制造的假体装置的钙化 阻断Ama可显著抑制牛心包的 通过选择的Gly残基的化学转化形成 丝氨酸残基。 将进行的具体研究包括：1） 含有Ama残基的肽单元的合成， 蛋白质中的金属结合位点，2）金属结合的测定 这些肽的性质，3）从模型研究中确定 通过自由基诱导的Gly羧化形成Ama残基 结构蛋白特别是牛1型胶原蛋白的残基 用于制造假体装置的Perceptor，4）开发 将暴露的Gly残基自由基转化为Ser的方法 用于抑制假体病理性钙化的残留物 5）确定抑制实际上与 阻断体内Ama的形成。 一个重要的健康相关结果将 开发一种牛心包改性方法， 其将抑制假体的体内病理性钙化 用于人体植入的器械。

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.