The pharmacological and toxicological effects of ethanol are in part determined by the rate of ethanol metabolism and the concentration of alcohol metabolites (acetaldehyde, acetate, and NADH). The levels of these metabolites are determined by the activities of alcohol and aldehyde metabolizing enzymes. The Structural Biology Core laboratory has offered services for the synthesis of recombinant alcohol and aldehyde metabolizing enzymes and for X-ray crystallographic analysis of pure proteins. In the coming period of support, this Core will also support research carried out by investigators with independent funding that will extend observations made by this and the Molecular Biology Core in the previous funding periods. The fundamental research question of the core has been: That are the structural determinants for the rate of alcohol or aldehyde oxidation and the substrate specificity for the different human alcohol and aldehyde dehydrogenases? The development of research tools to further address these important issues will be the focus of services provided by the Core in the coming funding period. The Core will continue to offer the services mentioned above. In particular, it will support the final phase of the crystal structure solution of ALDH2. In a new direction, it will support the generation of cells expressing alcohol and aldehyde dehydrogenases to serve as models of alcohol and aldehyde metabolism. These cells will be utilized to elucidate the factors that determine the rates of metabolism of a variety of alcohols and aldehydes (e.g., retinoids). These studies will provide a better understanding of the effects of the known enzyme variants on alcohol metabolism and the effects of ethanol on this metabolism. Cells expressing other proteins relevant to alcohol research will also be generated.
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