Abstract

Many proteins in the eukaryotic cell are modified by O-linked N-acetylglucosamine (O-GlcNAc) on serines and threonines. O-GlcNAcylation has been shown to be important for regulation of the cell cycle, DNA transcription and translation, insulin sensitivity and protein degradation. Misregulation of O-GlcNAcylation is associated with diabetes and Alzheimer’s disease. Two enzymes are involved in the dynamic cycling of this posttranslational modification, the O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). It has been demonstrated that this posttranslational modification occurs on some serines/threonines that are also known phosphorylation sites for a number of key kinases, giving rise to the “yin-yang” theory, that proposes that O-GlcNAcylation is a means of regulating protein phosphorylation. Work in my group is aimed at studing this mechanism. We are studying the structures of OGA and OGT to gain insight into substrate recognition, and we have developed highly potent and selective inhibitors to study O-GlcNAcylation in live cells. Using these tools were are currently studying the role of O-GlcNAc in signalling pathways involved in diabetes, cancer and Alzheimer’s disease.