O-Linked N-acetylglucosamine transferase (OGT) is responsible for the addition of β-N-acetylglucosamine (GlcNAc) to over 1,000 proteins in mammalian cells, and the addition of these O-GlcNAc groups to target proteins has been shown to affect localization, stability, enzymatic activity, and interactions with other biomolecules. Misregulation of OGT has been linked to cancer, diabetes, heart disease, and Alzheimer’s disease. However, studies of how OGT misregulation contributes to disease have been limited, in part because fast-acting chemical tools to manipulate OGT activity in cells have remained elusive. SAR efforts have led to a series of probe compounds, some of which exhibit nanomolar Kds, are cell permeable, and exhibit no notable toxicity. Crystal structures of several cocomplexes reveal that the quinolinone-6-sulfonamide portion of the molecules serves as a uridine mimic. These inhibitors make possible future studies to elucidate the role of OGT in disease pathology and to test whether OGT inhibition may offer a therapeutic benefit. In my independent career, I hope to study the chemical biology of glycosyltransferases involved in bacterial cell wall biosynthesis and to teach classes at the interface of chemistry and biology.

Developing new tools for the study of O-GlcNAc transferase in disease

254th National Meeting (2017)

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