| O‑linked N‑acetylglucosamine (O‑GlcNAc) is a dynamic monosaccharide modification added to serine and threonine residues of nuclear, cytoplasmic, and mitochondrial proteins by the single enzyme O‑GlcNAc transferase (OGT) and removed by O‑GlcNAcase (OGA), forming a two‑enzyme cycle that is tightly coupled to cellular nutrient status through the hexosamine biosynthetic pathway and UDP‑GlcNAc availability. The modification occurs on hundreds to thousands of regulatory proteins, including transcription factors, kinases, phosphatases, chromatin remodelers, cytoskeletal components, and metabolic enzymes, and often shares or flanks the same serine/threonine residues targeted by phosphorylation, creating reciprocal or cooperative O‑GlcNAc–phosphate “switches” that tune protein activity, subcellular localization, and interaction networks in response to glucose, amino acids, fatty acids, and stress signals. In signaling pathways, O‑GlcNAcylation modulates key nodes, including components of the insulin pathway, where elevated O‑GlcNAc on IRS‑1 and Akt interferes with their phosphorylation and attenuates downstream insulin signaling, linking chronic nutrient excess and increased flux through the hexosamine pathway to insulin resistance and type 2 diabetes phenotypes. On transcriptional and epigenetic regulation, OGT associates with chromatin at promoters and enhancers and modifies histones and transcriptional regulators, integrating nutrient cues into control of gene expression programs that affect cell growth, stress responses, and differentiation. In neurobiology, widespread O‑GlcNAcylation of neuronal proteins participates in synaptic function and proteostasis, and reductions in brain O‑GlcNAc, driven by regional glucose hypometabolism, correlate with increased phosphorylation and aggregation‑prone behavior of tau and other Alzheimer‑linked proteins; pharmacologic elevation of O‑GlcNAc on tau decreases its phosphorylation at disease‑relevant sites and alters its aggregation properties in experimental systems, identifying O‑GlcNAc cycling as a mechanistic link between metabolism and neurodegeneration. Dysregulated O‑GlcNAcylation is consistently associated with diabetes and its complications, cardiovascular dysfunction, cancer, and neurodegenerative disease. |
