The Rockefeller University Press

Protein modification by O-linked -N-acetyl glucosamine (O-GlcNAc) has rapidly emerged as a major cellular signaling mechanism rivaling protein phosphorylation in terms of the number of modified targets (Fig. 1 A). O-GlcNAc is an uncharged acetylated hexosamine sugar attached through a glycosyl linkage to hydroxyl-containing amino acids that adds bulk to modified amino acid side chains. O-GlcNAc is added to and removed from nucleocytoplasmic and mitochondrial target proteins by the intracellular enzymes O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). These O-GlcNAc cycling enzymes are distinct from the glycosyltransferases and glycosidases sequestered within the lumen of endomembrane organelles or routed to the cell surface. The enzymatic machinery catalyzing O-GlcNAc addition and removal bear some structural resemblanc