A Selective Inhibitor Gal-PUGNAc of Human Lysosomal β-Hexosaminidases Modulates Levels of the Ganglioside GM2 in Neuroblastoma Cells

Authors

  • Keith A. Stubbs Dr.,

    1. Department of Chemistry, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia V5A 1S6 (Canada), Fax: (+1) 604-291-3765
    2. Current address: Chemistry M313, School of Biomedical, Biomolecular and Chemical Sciences, University of Western Australia, 35 Stirling Highway, Crawley, Western Australia 6009 (Australia), Fax: (+618) 6488-1005
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  • Matthew S. Macauley,

    1. Department of Chemistry, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia V5A 1S6 (Canada), Fax: (+1) 604-291-3765
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  • David J. Vocadlo Prof.

    1. Department of Chemistry, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia V5A 1S6 (Canada), Fax: (+1) 604-291-3765
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  • K.A.S. and M.S.M. contributed equally to this work. We thank Don Mahuran and Michael Tropak for their generous gift of human HEXA and HEXB, Rosemary Cornell for the HPTLC plates, and Cara-Lynne Schengrund for useful discussions on the use of SK-N-SH cells and HPTLC of gangliosides. This work was supported by a grant from the Natural Sciences and Engineering Research Council of Canada (NSERC). D.J.V. is a scholar of the Michael Smith Foundation of Health Research (MSFHR) and a Tier II Canada Research Chair in Chemical Glycobiology. K.A.S. is supported by a Discovery project grant from the Australian Research Council. M.S.M. is a recipient of a senior scholarship from the NSERC and MSFHR.

Abstract

Gal-PUGNAc (see picture), a highly selective inhibitor for β-hexosaminidases HEXA and HEXB is cell-permeable and modulates the activity of HEXA and HEXB in tissue culture, increasing ganglioside GM2 levels. Gal-PUGNAc should allow the role of these enzymes to be studied at the cellular level without generating a complex chemical phenotype from concomitant inhibition of O-GlcNAcase.

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