As a focus of this research, conformationally constrained glycopeptides will be used as probes of the recognition of glycoproteins by the glycotransferases that construct core structures of O-linked oligosaccharides. The tranferase chosen for detailed study is that responsible for biosynthesizing Core 1 disaccharide (Core 1 GalTase). Core 1 GalTase is known to selectivity glycosylate GalNAc motifs in particular protein backbone sequences and secondary structures. Compounds which correspond to conformationally locked, low energy rotamers around the torsional angle x2 of the parent GalNAc, will be synthesized and incorporated into peptides. These glycopeptides will then be evaluated as substrates or inhibitors of Core 1 GalTase. The findings will be used to elucidate the three dimensional array of peptide and carbohydrate determinants in the substrate that constitute the binding epitome for Core 1 GalTase and to develop a model for how this equates with information transfer from protein to carbohydrate domains. The primary focus of the educational will be the development of a bachelors/masters degree program with offerings in synthetic chemistry, analytical chemistry, environmental chemistry and biotechnology. With this Faculty Early Development (CAREER) award, the Organic and Macromolecular Chemistry Program is supporting the research and educational activities of Dr. Randall L. Halcomb of the Department of Chemistry at the University of Colorado, Boulder. Professor Halcomb will focus his research efforts on combining the tools of organic chemistry with biochemistry and structural biology to design and synthesize conformationally constrained glycopeptides as probes of the recognition of glycoproteins by the glycotransferases that construct core structures of O-linked oligosaccharides. Glycoylation is a ubiquitous modification of proteins and is associated with a number of processes within the cell and at the cell surface, such as protein transport, cell adhesion and signal transduction. The education plan will center on the development of a bachelors/masters degree program in chemistry.
