AMINOMALONIC ACID AND THE CALCIFICATION OF PROTEIN

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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.