Harvard Medical School
The Split Personality of Human O‐GlcNAc Transferase
O-GlcNAc Transferase (OGT) is a glycosyltransferase essential for the viability of most multicellular organisms, including mammals. It catalyzes the attachment of N-acetylglucosamine (GlcNAc) to serines and threonines of
nuclear and cytoplasmic proteins, resulting in changes in protein localization, stability, and interactions. Protein O-GlcNAc levels are responsive to cellular glucose concentration, and chronically elevated O-GlcNAc levels
are observed in both cancer and diabetes and are associated with widespread changes in gene expression. While the importance of OGT in the biology of multicellular organisms is clear, the molecular mechanisms underlying its effects remain poorly understood. Recently, OGT was reported to catalyze another post-translational modification: the cleavage of the essential cell cycle regulator host cell factor 1(HCF-1). Cleavage is required for proper HCF-1 function.
My laboratory has been working on the chemistry of OGT in order to lay the groundwork for exploring its biology. I will talk about our structural work on OGT and describe what we have learned about the mechanism of O-GlcNAcylation and HCF-1 cleavage. I will also describe the development of cell permeable OGT inhibitors and show how they bind to the enzyme. Finally, I will touch on how our biochemical studies have provided information that may allow us to address a key question: why is OGT essential for the viability of all dividing mammalian cells?