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    Spiro-epoxyglycosides as Activity-Based Probes for Glycoside Hydrolase Family 99 Endomannosidase/Endomannanase

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    Author
    Schroder, SP; Kallemeijn, WW; Debets, MF; Hansen, T; Sobala, LF; Hakki, Z; Williams, SJ; Beenakker, TJM; Aerts, JMFG; van der Marel, GA; ...
    Date
    2018-07-11
    Source Title
    Chemistry: A European Journal
    Publisher
    WILEY-V C H VERLAG GMBH
    University of Melbourne Author/s
    Williams, Spencer
    Affiliation
    School of Chemistry
    Metadata
    Show full item record
    Document Type
    Journal Article
    Citations
    Schroder, S. P., Kallemeijn, W. W., Debets, M. F., Hansen, T., Sobala, L. F., Hakki, Z., Williams, S. J., Beenakker, T. J. M., Aerts, J. M. F. G., van der Marel, G. A., Codee, J. D. C., Davies, G. J. & Overkleeft, H. S. (2018). Spiro-epoxyglycosides as Activity-Based Probes for Glycoside Hydrolase Family 99 Endomannosidase/Endomannanase. CHEMISTRY-A EUROPEAN JOURNAL, 24 (39), pp.9983-9992. https://doi.org/10.1002/chem.201801902.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/255266
    DOI
    10.1002/chem.201801902
    Abstract
    N-Glycans direct protein function, stability, folding and targeting, and influence immunogenicity. While most glycosidases that process N-glycans cleave a single sugar residue at a time, enzymes from glycoside hydrolase family 99 are endo-acting enzymes that cleave within complex N-glycans. Eukaryotic Golgi endo-1,2-α-mannosidase cleaves glucose-substituted mannose within immature glucosylated high-mannose N-glycans in the secretory pathway. Certain bacteria within the human gut microbiota produce endo-1,2-α-mannanase, which cleaves related structures within fungal mannan, as part of nutrient acquisition. An unconventional mechanism of catalysis was proposed for enzymes of this family, hinted at by crystal structures of imino/azasugars complexed within the active site. Based on this mechanism, we developed the synthesis of two glycosides bearing a spiro-epoxide at C-2 as electrophilic trap, to covalently bind a mechanistically important, conserved GH99 catalytic residue. The spiro-epoxyglycosides are equipped with a fluorescent tag, and following incubation with recombinant enzyme, allow concentration, time and pH dependent visualization of the bound enzyme using gel electrophoresis.

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