AMINOMALONIC ACID AND THE CALCIFICATION OF PROTEIN

在细菌碱性水解物中发现了氨基酸 蛋白质、钙化的人体动脉蛋白质以及钙化假体中的蛋白质 由牛心包制成的装置。基于初步的 有证据表明，结构蛋白中Ama残基的形成是 推测与这些细胞的病理性钙化有关 动脉粥样硬化等疾病中的蛋白质和假体设备中的蛋白质 人造心脏瓣膜。更具体地说，提案规定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 残基很可能以簇状形式存在，是钙离子的结合部位。 因此，使磷酸钙结晶成核，3) 自由基羧化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)假体装置的钙化 通过阻断AMA可显著抑制牛心包的释放 通过选定的甘氨酸残基的化学转化形成 丝氨酸残留物。将进行的具体研究包括：1) 含有Ama残基的多肽单元的合成 蛋白质中的金属结合部位，2)金属结合的测定 这些多肽的性质，3)从模型研究中确定 自由基诱导甘氨酸羧化形成AmA残基 牛结构蛋白尤其是1型胶原的残留量 利用过碳粉制造假体，4)研制 甘氨酸暴露残基自由基转化为丝氨酸的方法 抑制假体病理性钙化的残留物 设备，以及5)确定抑制实际上与 阻断体内AMA的形成。一项与健康相关的重要结果将 一种牛心包的改性工艺的开发 它会抑制假体在体内的病理性钙化 用于人体植入的设备。

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.