API

Event: 1604

Key Event Title

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Inhibition of N-linked glycosylation

Short name

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Inhibition of N-linked glycosylation

Biological Context

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Level of Biological Organization
Molecular

Cell term

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Organ term

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Key Event Components

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Process Object Action

Key Event Overview


AOPs Including This Key Event

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AOP Name Role of event in AOP
Inhibition of N-linked glycosylation leads to liver injury MolecularInitiatingEvent

Stressors

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Taxonomic Applicability

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Life Stages

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Sex Applicability

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Key Event Description

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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

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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

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Evidence for Perturbation by Stressor


Overview for Molecular Initiating Event

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References

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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.