BIOLOGY OF SIALIC ACID SUBSTITUTIONS

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Many specific biological functions have been attributed to sialic acids. However, most studies of sialic acids do not take into account the diversity generated by modifications of the parent molecule, such as 0-acetylation of the side chain. During the prior funding period, we have developed new and sensitive methods for the analysis of modified sialic acids, identified some new and unexpected molecules, studied sialic acid:O-acetyltransferases from E.Coli., rat liver and human melanoma, identified and characterized sialic acid-specific 0-acetyl-esterases, studied the biosynthesis and turnover of the N-glycolyl group of sialic acids, and discovered a novel de-N-acetylation/re-N-acetylation reaction in melanoma gangliosides. Most recently, we have developed a novel approach to abrogate O-acetylation in the early mouse embryo, and in selected tissues of transgenic mice. In the upcoming grant period, we will focus our attention upon the following: 1. Purification, reconstitution and characterization of the rat liver Sialic Acid O-acetyltransferase(s). 2. Subcellular distribution of O-acetylated sialic acids, and the related enzymes in rat liver. 3. Purification, reconstitution and properties of human melanoma Sialic Acid O-acetyltransferase(s). 4. Mechanisms for de-N-acetylation and re-N-acetylation of sialic acids on gangliosides. 5. Molecular cloning of cDNAs encoding sialic acid specific O-acetyltransferase(s). 6. Abrogation of O-acetylation in the early mouse embryo. 7. Abrogation of O-acetylation in selected tissues of transgenic mice. In the long run, these studies will help us to understand the biological roles of sialic acids and their modifications in health and disease. Our findings to date implicate these molecules in a variety of important roles, including protection from microbial organisms on mucosal surfaces, the modulation of complement activation, the expression of oncofetal antigens in various tumors, and the regulation of cell-cell interaction during the development of certain organs.