Generation of specific deoxynojirimycin-type inhibitors of the non- lysosomal glucosylceramidase

Herman S. Overkleeft, G. Herma Renkema, Jolanda Neele, Paula Vianello, Irene O. Hung, Anneke Strijland, Alida M. Van Der Burg, Gerrit Jan Koomen, Upendra K. Pandit, Johannes M F G Aerts

Research output: Contribution to journalArticle

Abstract

The existence of a non-lysosomal glucosylceramidase in human cells has been documented (van Weely, S., Brandsma, M., Strijland, A., Tager, J. M., and Aerts, J. M. F. G. (1993) Biochim. Biophys. Acta 1181, 55-62). Hypothetically, the activity of this enzyme, which is localized near the cell surface, may influence ceramide-mediated signaling processes. To obtain insight in the physiological importance of the non-lysosomal glucosylceramidase, the availability of specific inhibitors would be helpful. Here we report on the generation of hydrophobic deoxynojirimycin (DNM) derivatives that potently inhibit the enzyme. The inhibitors were designed on the basis of the known features of the non-lysosomal glucosylceramidase and consist of a DNM moiety, an N-alkyl spacer, and a large hydrophobic group that promotes insertion in membranes. In particular, N-(5-adamantane-1-yl- methoxy)pentyl)-DNM is a very powerful inhibitor of the non-lysosomal glucosylceramidase at nanomolar concentrations. At such concentrations, the lysosomal glucocerebrosidase and α-glucosidase, the glucosylceramide synthase, and the N-linked glycantrimming α-glucosidases of the endoplasmic reticulum are not affected.

Original languageEnglish
Pages (from-to)26522-26527
Number of pages6
JournalJournal of Biological Chemistry
Volume273
Issue number41
DOIs
Publication statusPublished - Oct 9 1998

ASJC Scopus subject areas

  • Biochemistry

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    Overkleeft, H. S., Renkema, G. H., Neele, J., Vianello, P., Hung, I. O., Strijland, A., Van Der Burg, A. M., Koomen, G. J., Pandit, U. K., & Aerts, J. M. F. G. (1998). Generation of specific deoxynojirimycin-type inhibitors of the non- lysosomal glucosylceramidase. Journal of Biological Chemistry, 273(41), 26522-26527. https://doi.org/10.1074/jbc.273.41.26522