Competitive and covalent inhibitors of human lysosomal retaining exoglucosidases

Imogen Z. Breen, Marta Artola, Liang Wu, Thomas Beenakker, Wendy A. Offen, Johannes M. F. G. Aerts, Gideon J. Davies, Herman S. Overkleeft

Research output: Chapter in Book/Report/Conference proceedingChapter


Deficiency in human acid glucosylceramidase (GBA1, a retaining β‐glucosidase) causes the lysosomal sphingolipid storage disorder Gaucher disease, whereas deficiency in human acid α‐glucosidase (GAA, a retaining α‐glucosidase) triggers the lysosomal glycogen storage disorder Pompe disease. Both enzymes process their substrate following a two‐step double‐displacement mechanism involving a covalent enzyme–substrate intermediate. Structural analysis of glycosidases complexed to substrates and inhibitors has provided insight into the reaction coordinates followed by glycosidases during catalytic hydrolysis and has assisted in the design of potent and selective inhibitors. Competitive and covalent inhibitors of both GBA1 and GAA have been developed in the past decades, for fundamental studies, as diagnostics tools, leads for drug development and therapeutic drugs for the clinical treatment of lysosomal storage diseases.
Original languageEnglish
Title of host publicationeLS
ISBN (Electronic)9780470015902
Publication statusPublished - 22 Jan 2018

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