THE METABOLISM AND FUNCTION OF THE POLYPRENOLS

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Glycoproteins are a very large class of proteins that have many diverse functions. Most of these proteins are assembled by the addition of a common or "core" oligosaccharide chain to an asparagine in the protein. The carbohydrate portion of this molecule is then modified by the removal and addition of various sugars until the appropriate compound is formed. The proposed research has as its objectives the collection of data that will enable us to understand the assembly of the "core" oligosaccharide and how it is eventually transferred to protein. This process is known to involve a series of reactions in which the carbohydrate intermediates are linked to cis-polyisoprenyl phosphates or pyrophosphates. This class of compound is called dolichol and, dispite the intense interest in glycoprotein metabolism, relatively little is known about the metabolism of these key intermediates. The experiments in this proposal are a continuation of our studies on the biosynthesis, phosphorylation, dephosphorylation, cellular and subcellular distribution, storage and excretion of dolichol. In addition, the reactions in which dolichol serves as an intermediate in the biosynthesis of glycoproteins will also be investigated. These experiments involve the chemical synthesis of radioactive dolichol derivatives as well as compounds similar to tunicamycin which inhibit glycoprotein biosynthesis. These compounds will be used as tools to aid us in dissecting the individual reactions in the overall process of glycoprotein biosynthesis so that they can be studied. Diabetes is a disease which has as one of its serious consequences the development of abnormal membrane structures that probably result from the production of abnormal glycoproteins. Experiments will be conducted with animals with streptazotocin-induced diabetes to see if the profound changes in carbohydrate and lipid metabolism produced by this disease have effects on reactions in the dolichol-mediated synthesis of glycoproteins that ultimately result in abnormal glycoproteins being produced.