O-GlcNAc transferase (OGT) is an essential mammalian glycosyltransferase that modifies intracellular proteins with a monosaccharide N-acetylglucosamine, called O-GlcNAcylation. Understanding OGT's function is critically important because this enzyme regulates numerous biological processes, and many of them become aberrant in human diseases. However, the precise role of OGT remains largely unclear due to a number of challenges. These include the fact that OGT glycosylates thousands of proteins without an apparent sequence motif and the dynamic changes of OGT's catalytic activity and substrate specificity (termed ?functional states?) in response to cellular conditions. Conventional O-GlcNAc detection is not suitable for direct characterizing the OGT enzyme or understanding its regulatory mechanism in cells. We have designed a conceptually new chemical probe that generates distinct modifications to report different functional states of OGT. Here, we propose to implement this probe to characterize the structural features of OGT that contribute to substrate recognition. In addition, we intend to develop cell-permeable, selective inhibitors and active site probes to investigate the biological roles of OGT and to profile the molecular signatures that underlying its dysfunction in cancer. The unique chemical tools established in this research program will provide innovative approaches and unprecedented insights to dissect the molecular basis underlying complex OGT biology and may discover new pathways leading to cancer.
O-GlcNAc transferase is an essential human enzyme. Its aberrant function has been detected in a wide variety of diseases, such as diabetes, Alzheimer's, and almost all types of cancer. This application outlines innovative chemical approaches to characterizing the dynamic function of this enzyme to facilitate our understanding of disease and designing new therapeutic strategies.
| Hu, Chia-Wei; Worth, Matthew; Fan, Dacheng et al. (2017) Electrophilic probes for deciphering substrate recognition by O-GlcNAc transferase. Nat Chem Biol 13:1267-1273 |
