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Glycosyltransferases and Cell Signaling |
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In eukaryotic cells, many nuclear and cytoplasmic proteins are glycosylated by an enzyme called OGT, which catalyzes formation of a β-linkage from a single O-GlcNAc to a serine or threonine residue. This process is reminiscent of phosphorylation because it is dynamic and modulated by external stimuli. While phosphoryation is regulated by hundreds of kinases and dozens of phosphatases, O-GlcNAc appears to be cycled by a single glycosyltransferase and a single glycosidase. O-GlcNAcylation mediates protein-protein interactions, regulates the activity of transcription factors, slows protein degradation, and plays a role in signaling pathways. Aberrant O-GlcNAcylation is implicated in a number of disease states, including Parkinson's disease, Alzheimer's disease, type II diabetes, and cancer. We have developed a high throughput screen for OGT inhibitors and have identified several small molecule inhibitors. Several of these inhibitors are active in cells and we are using them as tools to dissect the functions of OGT. We are also working toward solving the crystal structure of the catalytic domain of OGT, which will facilitate the design of better inhibitors that may have therapeutic utility.
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Selected Publications: |
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"Discovery of O-GlcNAc Transferase Inhibitors" Gross BJ, Kraybill BC, and Walker* S. J Am Chem Soc 2005; 127:14588-14589.
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