Chemical tools to explore nutrient-driven O-GlcNAc cycling

Abstract

Posttranslational modifications (PTM) including glycosylation, phosphorylation, acetylation, methylation and ubiquitination dynamically alter the proteome. The evolutionarily conserved enzymes O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) and O-GlcNAcase are responsible for the addition and removal, respectively, of the nutrient-sensitive PTM of protein serine and threonine residues with O-GlcNAc. Indeed, the O-GlcNAc modification acts at every step in the “central dogma” of molecular biology and alters signaling pathways leading to amplified or blunted biological responses. The cellular roles of OGT and the dynamic PTM O-GlcNAc have been clarified with recently developed chemical tools including high-throughput assays, structural and mechanistic studies and potent enzyme inhibitors. These evolving chemical tools complement genetic and biochemical approaches for exposing the underlying biological information conferred by O-GlcNAc cycling.

• O-GlcNAc
• O-GlcNAc transferase
• OGT's activity assays
• OGT's catalytic mechanism
• OGT's inhibitors

Acknowledgements

We acknowledge helpful comments from the Hanover and Krause laboratories and support from the Intramural NIDDK program including the NIDDK Chemical Biology Core.