O-Linked β-N-acetylglucosamine

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O-Linked β-N-acetylglucosamine (O-GlcNAc) is an intracellular carbohydrate that dynamically modifies the amino acids serine and threonine through their hydroxyl moieties on nuclear and cytoplasmic proteins. As a form of protein glycosylation, it differs from most other forms in three aspects: first, it occurs exclusively within the nuclear and cytoplasmic compartments of the cell; secondly, it is generally not elongated or modified to form more complex structures; lastly it is attached and removed multiple times in the life of a polypeptide, often cycling at rapid, different rates on different sites.


O-linked GlcNAc was first discovered in 1983; when probing for GlcNAc-terminating glycoconjugates in thymocytes, lymphocytes and macrophages, analyses showed most galactosylated (glycosylation using galactose) glycans existed within the cell as single O-linked GlcNAc varieties.

Protein glycosylation has long been regarded not to occur in the cytoplasmic/nuclear compartments of the cell.[1] However, research during the past two decades has clearly shown that O-GlcNAc is one of the most abundant posttranslational modifications within the nucleocytoplasmic compartments of all members of the Metazoan division, including animals, the viruses that infect them, and plants. It is found on hundreds, if not thousands, of nucleocytoplasmic proteins, and in fact many of the most heavily studied proteins in biology are O-GlcNAcylated. There has been no evidence of O-GlcNAc outside of cells.


O-GlcNAc cycles rapidly on and off most proteins, unlike most mature glycans, depending on both the protein and the protein site it attaches to. External signals and inhibitors of O-GlcNAcase have also been shown to affect O-GlcNAc cycling, and rates were recently quantified to have half-lives of 1 minute or less.

O-GlcNAcylation and phosphorylation have a complex signaling relationship. The same enzyme complex that removes O-phosphate is indicated to be the same enzyme complex that attaches O-GlcNAc.[2] In some cases, though O-GlcNAc and O-phosphate occur at adjacent, separate sites, they still appear to be reciprocal.


O-GlcNAc has been found expressed in every human tissue and is believed to be a key component in the regulatory cycle of modification of serine and threonine residues on nuclearcytoplasmic proteins.[3]

Nucleocytoplasmic O-β-GlcNAc in particular has been found in all multicellular organisms investigated, including fungi, worms, insects, plants and humans. Everywhere that serine and threonine O-phosphorylation has been found, O-GlcNAc occurs.


Research about O-GlcNAc is particularly relevant to chronic human diseases including diabetes, cardiovascular disease, neurodegenerative disorders, and cancer, the last of which is heavily dependent on glycolysis and phosphorylation. Additionally, O-GlcNAcylation plays a crucial role in regulating tau, a microtubule protein whose pathology is correlated to the severity of dementia in Alzheimer's disease.[4]

See also[edit]


  1. ^ Comer, F.I.; Hart, G.W. (2000). "O-glycosylation of nuclear and cytosolic proteins. Dynamic interplay between O-GlcNAc and O-phosphate". J. Biol. Chem. 275: 29179–29182. doi:10.1074/jbc.r000010200. PMID 10924527.
  2. ^ Hart GW, Akimoto Y. The O-GlcNAc Modification. In: Varki A, Cummings RD, Esko JD, et al., editors. Essentials of Glycobiology. 2nd edition. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 2009. Chapter 18. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1954/?report=classic
  3. ^ Spiro, RG (April 2002). "Protein glycosylation: nature, distribution, enzymatic formation, and disease implications of glycopeptide bonds". Glycobiology. 12: 43R–56R. doi:10.1093/glycob/12.4.43r. PMID 12042244.
  4. ^ Liu, Fei; et al. (2004). "O-GlcNAcylation Regulates Phosphorylation of Tau: A Mechanism Involved in Alzheimer's Disease". Proceedings of the National Academy of Sciences of the United States of America. 101 (29): 10804–10809. doi:10.1073/pnas.0400348101. PMC 490015. PMID 15249677.