To the extent possible under law, AOP-Wiki has waived all copyright and related or neighboring rights to KE:1604
Key Event Title
Inhibition of N-linked glycosylation
|Level of Biological Organization|
Key Event Components
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD Status|
|Inhibition of N-linked glycosylation leads to liver injury||MolecularInitiatingEvent||Arthur Author (send email)||Under development: Not open for comment. Do not cite|
Key Event Description
The ER, glycosylation is performed to newly synthesized unfolded proteins. Misfolded proteins recognized by ER- associated degradation (ERAD). (Stein, Ruggiano, Carvalho, & Rapoport, 2014)
The terminal glucoses and mannoses in combination with lectin receptors maintain correct folding of nascent polypeptide and contribute in the elimination of misfolded proteins (Schwarz & Aebi, 2011)(Adnan et al., 2016)(Araki & Nagata, 2012)(Shao & Hegde, 2016)(Kim, Spear, & Ng, 2005)
This quality control of protein folding is glycosylation directed. Misfolded proteins that are unglycosylated fail to be recognized by ERAD (Shental-Bechor & Levy, 2008)
Glycosylation inhibition can be achieved through direct inhibition of the biosynthesis or the processing of N-Linked oligosaccharide chains. Enzymes that synthesize N-linked oligosaccharide chain are targets for inhibition of glycosylation.
Tunicamycin inhibits N-Linked glycosylation by blocking the transfer of N-acetylglucosamine-1-phosphate (GlcNAc-1-P) from UDP-GlcNAc to dolichol-P. Amphomycin, a lipopeptide, inhibits dolichol-P-mannose synthesis by apparently forming complexes with the carrier lipid dolichol-P. (Mcdowell et al., 1988) Elbein et al 1987,Varki et al 2009)
How It Is Measured or Detected
Glycosylation mutants (Esko et al 2017)
Efficacy of inhibition of the oligosaccharide processing can be measured by TCA precipitation or endo H digestion analysis of radiolabeled cells. (Powell, 1995) (Kim et al., 2005)
Alteration in levels of protein glycosylation can be measured using a lectin microarray. (Liu et al., 2017)
Bioluminescent N-linked-glycosylation reporters (Contessa et al., 2012)
Domain of Applicability
Evidence for Perturbation by Stressor
Overview for Molecular Initiating Event
Adnan, H. et al. (2016) ‘Endoplasmic reticulum-targeted subunit toxins provide a new approach to rescue misfolded mutant proteins and revert cell models of genetic diseases’, PLoS ONE, 11(12), pp. 1–19. doi: 10.1371/journal.pone.0166948.
Aebi, M. (2013) ‘N-linked protein glycosylation in the ER’, Biochimica et Biophysica Acta - Molecular Cell Research. Elsevier B.V., 1833(11), pp. 2430–2437. doi: 10.1016/j.bbamcr.2013.04.001.
Araki, K. and Nagata, K. (2012) ‘SUP: Protein folding and quality control in the ER.’, Cold Spring Harbor perspectives in biology, 4(8), p. a015438. doi: 10.1101/cshperspect.a015438.
Buckley, B. J. and Whorton, A. R. (1997) ‘Tunicamycin increases intracellular calcium levels in bovine aortic endothelial cells’, Am.J.Physiol, 273(0002–9513 (Print)), pp. C1298–C1305.
Contessa, J. N. et al. (2012) ‘Biosynthesis is a Novel Target for Cancer Therapy’, 16(12), pp. 3205–3214. doi: 10.1158/1078-0432.CCR-09-3331.Molecular.
Elbein, A.D., Pan, Y.T., Solf, R., and Vosbeck, K. (1983). Effect of swasinone, an inhibitor of glyciprotein processing, on cultured mammalian cells. J. Cell Physiol. 115:265-275.
Esko JD, Stanley P. Glycosylation Mutants of Cultured Mammalian Cells. 2017. In: Varki A, Cummings RD, Esko JD, et al., editors. Essentials of Glycobiology [Internet]. 3rd edition. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 2015-2017. Chapter 49.
Esko JD, Bertozzi C, Schnaar RL. Chemical Tools for Inhibiting Glycosylation. 2017. In: Varki A, Cummings RD, Esko JD, et al., editors. Essentials of Glycobiology [Internet]. 3rd edition. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 2015-2017. Chapter 55.
Kim, W., Spear, E. D. and Ng, D. T. W. (2005) ‘Yos9p detects and targets misfolded glycoproteins for ER-associated degradation’, Molecular Cell, 19(6), pp. 753–764. doi: 10.1016/j.molcel.2005.08.010.
Li, K. et al. (2011) ‘Repression of N-glycosylation triggers the unfolded protein response (UPR) and overexpression of cell wall protein and chitin in aspergillus fumigatus’, Microbiology, 157(7), pp. 1968–1979. doi: 10.1099/mic.0.047712-0.
Lopez-Sambrooks, C. et al. (2016) ‘Oligosaccharyltransferase inhibition induces senescence in RTK-driven tumor cells’, Nature Chemical Biology, 12(12), pp. 1023–1030. doi: 10.1038/nchembio.2194.
Mcdowell, W. et al. (1988) ‘in influenza-virus-infected cells by x-D-mannopyranosylmethyl-’, 255, pp. 991–998.
Powell, L. (1995) ‘Inhibition of N-Linked Glycosylation’, Current Protocols in Immunology, 12(1995), pp. 1–12.
Salzberger, W. et al. (2015) ‘Influence of glycosylation inhibition on the binding of KIR3DL1 to HLA-B∗57:01’, PLoS ONE. doi: 10.1371/journal.pone.0145324.
Schwarz, F. and Aebi, M. (2011) ‘Mechanisms and principles of N-linked protein glycosylation’, Current Opinion in Structural Biology. Elsevier Ltd, 21(5), pp. 576–582. doi: 10.1016/j.sbi.2011.08.005.
Shao, S. and Hegde, R. S. (2016) ‘Target Selection during Protein Quality Control’, Trends in Biochemical Sciences. Elsevier Ltd, 41(2), pp. 124–137. doi: 10.1016/j.tibs.2015.10.007.
Shental-Bechor, D. and Levy, Y. (2008) ‘Effect of glycosylation on protein folding: A close look at thermodynamic stabilization’, Proceedings of the National Academy of Sciences, 105(24), pp. 8256–8261. doi: 10.1073/pnas.0801340105.
Stein, A. et al. (2014) ‘Key Steps in ERAD of Luminal ER Proteins Reconstituted with Purified Components’, Cell. doi: 10.1016/j.cell.2014.07.050.
Varki A, Cummings RD, Esko JD, et al., editors. Essentials of Glycobiology. 2nd edition. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 2009. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1908/
Wojtowicz, K. et al. (2012) ‘Inhibitors of N-glycosylation as a potential tool for analysis of the mechanism of action and cellular localisation of glycoprotein P’, Acta Biochimica Polonica, 59(4), pp. 445–450.