OGlcNAcylation

O-GlcNAcylation is a dynamic, reversible post-translational modification in which a single N-acetylglucosamine (GlcNAc) moiety is covalently attached to serine or threonine residues of intracellular, predominantly nuclear and cytoplasmic, proteins. The process is catalyzed by O-GlcNAc transferase (OGT) and reversed by O-GlcNAcase (OGA). Unlike extracellular glycosylation, O-GlcNAc cycling occurs within the nucleus and cytoplasm and does not involve the secretory pathway.

UDP-GlcNAc, produced by the hexosamine biosynthetic pathway from glucose and other nutrients, serves as the donor substrate for OGT. OGT exists in several isoforms, including a nucleocytoplasmic variant, and OGA is a hydrolase encoded by the MGEA5 gene. The O-GlcNAc modification often shows reciprocal relationship with phosphorylation, a form of crosstalk that enables rapid integration of nutrient and stress signals.

Functionally, O-GlcNAcylation regulates protein activity, stability, and interactions, and influences processes such as transcription, chromatin remodeling, signaling pathways, proteostasis, stress responses, and circadian rhythm. Many transcription factors, RNA polymerase II, histones, and metabolic or cytoskeletal enzymes are reported substrates. The modification responds to cellular nutrient status and stress, enabling coordinated cellular regulation.

Detection and study of O-GlcNAcylation rely on specific antibodies, lectin-based methods, and mass spectrometry for site mapping. Chemical and metabolic labeling techniques, including chemoenzymatic tagging, have expanded the ability to identify O-GlcNAc sites and characterize cycling dynamics.

Biological importance is indicated by essential roles in development and homeostasis; global loss of OGT is lethal in mice, and dysregulation of O-GlcNAc cycling is linked to metabolic disorders and neurodegenerative diseases, notably via interactions with phosphorylation pathways such as tau in Alzheimer's disease. O-GlcNAcylation remains an active area of research due to its pervasive regulatory functions and metabolic coupling.