This research focuses on metal-catalyzed oxidative modification of biopolymers, especially of proteins. The reaction is enabled by the binding of a metal such as iron or copper to a cation binding site on the targeted protein. Oxygen reacts at that site to generate an activated species which then oxidizes amino acid residues at the binding site. This oxidation leads to an apparently irreversible, covalent modification of proteins which has been implicated in important physiologic and pathologic processes. These include the aging processes, arthritis, hypertension, intracellular protein turnover, oxygen toxicity, and reperfusion injury after ischemia. Determination of the actual roles of oxidative modification in these processes requires development of specific assays for modified proteins, identification of the structural and functional changes induced by modification, and understanding of factors which modulate the rate and specificity of oxidative modification in vivo. These are the current aims of this project. In general, oxidatively-modified enzymes lose catalytic activity and become susceptible to proteolytic degradation. The cation binding site is weakened or destroyed and carbonyl groups are introduced into the side chains of the amino acid residues. These carbonyl groups are considered the hallmark of metal-catalyzed oxidative modification. Assays have been developed which permit detection and quantitation of these protein-bound carbonyl groups. Such assays are now being applied to assess the extent of oxidative modification of proteins in human disease states. Studies designed to specifically inactivate components of the human immunodeficiency virus are also in progress. Such studies have led to the unexpected discovery that low concentrations of copper rapidly inactivate the viral protease. Active protease is essential for viral replication, and thus, this finding has potential therapeutic value in AIDS.
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