O-GlcNAc

O-GlcNAc is a post-translational modification found on serine and threonine residues defined by a β-glycosidic bond between the side-chain hydroxyl and N-acetylglucosamine. GlcNAc moiety shown in red.

O-GlcNAc (short for O-linked GlcNAc or O-linked β-N-acetylglucosamine) is a reversible enzymatic post-translational modification that is found on serine and threonine residues of nucleocytoplasmic proteins. The modification is characterized by a β-glycosidic bond between the hydroxyl group of serine or threonine side chains and N-acetylglucosamine (GlcNAc). O-GlcNAc differs from other forms of protein glycosylation: (i) O-GlcNAc is not elongated or modified to form more complex glycan structures, (ii) O-GlcNAc is almost exclusively found on nuclear and cytoplasmic proteins rather than membrane proteins and secretory proteins, and (iii) O-GlcNAc is a highly dynamic modification that turns over more rapidly than the proteins which it modifies. O-GlcNAc is conserved across metazoans.[1]

Serine in a polypeptide with no modifications (top) and with an O-GlcNAc modification (bottom). (PDB: 4GYW)

Due to the dynamic nature of O-GlcNAc and its presence on serine and threonine residues, O-GlcNAcylation is similar to protein phosphorylation in some respects. While there are roughly 500 kinases and 150 phosphatases that regulate protein phosphorylation in humans, there are only 2 enzymes that regulate the cycling of O-GlcNAc: O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) catalyze the addition and removal of O-GlcNAc, respectively.[2] OGT utilizes UDP-GlcNAc as the donor sugar for sugar transfer.[3]

First reported in 1984, this post-translational modification has since been identified on over 5,000 proteins.[4][5] Numerous functional roles for O-GlcNAcylation have been reported including crosstalking with serine/threonine phosphorylation, regulating protein-protein interactions, altering protein structure or enzyme activity, changing protein subcellular localization, and modulating protein stability and degradation.[1][6] Numerous components of the cell's transcription machinery have been identified as being modified by O-GlcNAc, and many studies have reported links between O-GlcNAc, transcription, and epigenetics.[7][8] Many other cellular processes are influenced by O-GlcNAc such as apoptosis, the cell cycle, and stress responses.[9] As UDP-GlcNAc is the final product of the hexosamine biosynthetic pathway, which integrates amino acid, carbohydrate, fatty acid, and nucleotide metabolism, it has been suggested that O-GlcNAc acts as a "nutrient sensor" and responds to the cell's metabolic status.[10] Dysregulation of O-GlcNAc has been implicated in many pathologies including Alzheimer's disease, cancer, diabetes, and neurodegenerative disorders.[11][12]

  1. ^ a b Zeidan, Quira; Hart, Gerald W. (2010-01-01). "The intersections between O-GlcNAcylation and phosphorylation: implications for multiple signaling pathways". Journal of Cell Science. 123 (1): 13–22. doi:10.1242/jcs.053678. ISSN 0021-9533. PMC 2794709. PMID 20016062.
  2. ^ Dias, Wagner B.; Cheung, Win D.; Hart, Gerald W. (2012-06-01). "O-GlcNAcylation of Kinases". Biochemical and Biophysical Research Communications. 422 (2): 224–228. doi:10.1016/j.bbrc.2012.04.124. ISSN 0006-291X. PMC 3387735. PMID 22564745.
  3. ^ Haltiwanger, RS; Holt, GD; Hart, GW (1990-02-15). "Enzymatic Addition of O-GlcNAc to Nuclear and Cytoplasmic Proteins. Identification of a Uridine diphospho-N-acetylglucosamine:peptide beta-N-acetylglucosaminyltransferase". Journal of Biological Chemistry. 265 (5): 2563–8. doi:10.1016/S0021-9258(19)39838-2. PMID 2137449.
  4. ^ Wulff-Fuentes E, Berendt RR, Massman L, Danner L, Malard F, Vora J, Kahsay R, Olivier-Van Stichelen S (January 2021). "The human O-GlcNAcome database and meta-analysis". Scientific Data. 8 (1): 25. Bibcode:2021NatSD...8...25W. doi:10.1038/s41597-021-00810-4. PMC 7820439. PMID 33479245.
  5. ^ Ma, Junfeng; Hart, Gerald W (2014-03-05). "O-GlcNAc profiling: from proteins to proteomes". Clinical Proteomics. 11 (1): 8. doi:10.1186/1559-0275-11-8. ISSN 1542-6416. PMC 4015695. PMID 24593906.
  6. ^ King, Dustin T.; Serrano-Negrón, Jesús E.; Zhu, Yanping; Moore, Christopher L.; Shoulders, Matthew D.; Foster, Leonard J.; Vocadlo, David J. (2022-03-09). "Thermal Proteome Profiling Reveals the O-GlcNAc-Dependent Meltome". Journal of the American Chemical Society. 144 (9): 3833–3842. doi:10.1021/jacs.1c10621. ISSN 1520-5126. PMC 8969899. PMID 35230102.
  7. ^ Kelly, WG; Dahmus, ME; Hart, GW (1993-05-15). "RNA Polymerase II Is a Glycoprotein. Modification of the COOH-terminal Domain by O-GlcNAc". Journal of Biological Chemistry. 268 (14): 10416–24. doi:10.1016/S0021-9258(18)82216-5. PMID 8486697.
  8. ^ Sakabe, K; Wang, Z; Hart, GW (2010-11-16). "Beta-N-acetylglucosamine (O-GlcNAc) Is Part of the Histone Code". Proceedings of the National Academy of Sciences of the United States of America. 107 (46): 19915–20. Bibcode:2010PNAS..10719915S. doi:10.1073/pnas.1009023107. PMC 2993388. PMID 21045127.
  9. ^ Levine, Z; Walker, S (2016-06-02). "The Biochemistry of O-GlcNAc Transferase: Which Functions Make It Essential in Mammalian Cells?". Annual Review of Biochemistry. 85: 631–57. doi:10.1146/annurev-biochem-060713-035344. PMID 27294441.
  10. ^ Ong, Qunxiang; Han, Weiping; Yang, Xiaoyong (2018-10-16). "O-GlcNAc as an Integrator of Signaling Pathways". Frontiers in Endocrinology. 9: 599. doi:10.3389/fendo.2018.00599. ISSN 1664-2392. PMC 6234912. PMID 30464755.
  11. ^ Cheng, Steven S.; Mody, Alison C.; Woo, Christina M. (2024-11-07). "Opportunities for Therapeutic Modulation of O-GlcNAc". Chemical Reviews. doi:10.1021/acs.chemrev.4c00417. ISSN 0009-2665.
  12. ^ Hart, Gerald W.; Slawson, Chad; Ramirez-Correa, Genaro; Lagerlof, Olof (2011-06-07). "Cross Talk Between O-GlcNAcylation and Phosphorylation: Roles in Signaling, Transcription, and Chronic Disease". Annual Review of Biochemistry. 80: 825–858. doi:10.1146/annurev-biochem-060608-102511. ISSN 0066-4154. PMC 3294376. PMID 21391816.