COVALENT MODIFICATION OF PROTEINS BY DISULFIRAM

Vanderbilt University, Nashville TN

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Abstract

The experiments in this proposal will determine the site and structure of the covalent modifications produced on proteins, including aldehyde dehydrogenase, by disulfiram and its metabolites using in vitro and in vivo systems. The results will assist in determining whether disulfiram inhibits aldehyde dehydrogenase preferentially through thiocarbamoylation. Determination of the mechanism of disulfiram- mediated inhibition of aldehyde dehydrogenase will assist in the design of more effective alcohol aversion therapies, development of biomarkers for monitoring disulfiram therapy, identification of susceptible individuals and determine if protein modification should be evaluated as a contributing mechanism for disulfiram-mediated neurotoxicity and hepatoxicity. Because of the structural similarities, these studies are also relevant to the biological effects of dithiocarbamates, monothiocarbamates, and dithiocarbamate disulfides used in agriculture and industry.