The Structural Basis of Glycosidase Inhibition by Five-Membered Iminocyclitols: The Clan A Glycoside Hydrolase Endoglycoceramidase as a Model System

Authors

  • Matthew E. C. Caines Dr.,

    1. Department of Biochemistry and Molecular Biology, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada, Fax: (+1) 604-822-5227
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    • These authors contributed equally to this work.

  • Susan M. Hancock Dr.,

    1. Department of Chemistry, University of British Columbia, Room W300, 6174 University Boulevard, Vancouver, BC V6T 1Z3, Canada, Fax: (+1) 604-822-8869
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    • These authors contributed equally to this work.

  • Chris A. Tarling Dr.,

    1. Department of Chemistry, University of British Columbia, Room W300, 6174 University Boulevard, Vancouver, BC V6T 1Z3, Canada, Fax: (+1) 604-822-8869
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  • Tanja M. Wrodnigg Dr.,

    1. Glycogroup, Institut für Organische Chemie, Technische Universität Graz, Stremayrgasse 16, 8010 Graz, Austria
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  • Robert V. Stick Prof.,

    1. School of Biomedical, Biomolecular and Chemical Sciences, University of Western Australia, Chemistry M313, 35 Stirling Highway, Crawley, WA 6009, Australia
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  • Arnold E. Stütz Prof.,

    1. Glycogroup, Institut für Organische Chemie, Technische Universität Graz, Stremayrgasse 16, 8010 Graz, Austria
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  • Andrea Vasella Prof.,

    1. Laboratory of Organic Chemistry, ETH Zürich, HCI H317 Wolfgang-Pauli-Strasse 10, 8093 Zürich, Switzerland
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  • Stephen G. Withers Prof.,

    1. Department of Chemistry, University of British Columbia, Room W300, 6174 University Boulevard, Vancouver, BC V6T 1Z3, Canada, Fax: (+1) 604-822-8869
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  • Natalie C. J. Strynadka Prof.

    1. Department of Biochemistry and Molecular Biology, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada, Fax: (+1) 604-822-5227
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  • The authors would like to thank the staff at Beamline 8.2.2 of the Advanced Light Source, Berkeley, USA, for expert assistance and the Royal Society (UK), CIHR, MSFHR, HHMI, CFI, NSERC, and the Protein Engineering Network of Centres of Excellence (PENCE) for financial support. Systematic names of compounds studied: cellobiose-like isofagomine 1 b: (3R,4R,5R)-4-(β-D-glucopyranosyl)oxy-3-hydroxy-5-(hydroxymethyl)piperidine; cellobiose-like imidazole 2 b: (5R,6R,7S,8S)-6-(β-D-glucopyranosyloxy)-5,6,7,8-tetrahydro-5-(hydroxymethyl)imidazo-[1,2-a]pyridine-7,8-diol; and the five-membered iminocyclitol 3 b: 1-(4-dimethylamino)benzoylamino-1,2,5-trideoxy-2,5-imino-D-mannitol.

Abstract

original image

Fünf passt auch: Die Kristallstruktur eines an Glycosidase gebundenen fünfgliedrigen Iminocyclitols wurde bestimmt (siehe Bild), und die Wechselwirkungen bei der Bindung dieses Inhibitors wurden mit denjenigen für die gängigen sechsgliedrigen Inhibitoren Isofagomin und Glucoimidazol und im Glycosyl-Enzym-Intermediat verglichen. Diese Daten können zu wirksameren und spezifischeren Glycosidase-Inhibitoren für therapeutische Anwendungen führen.

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