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Gaucher disease is caused by mutations in human acid β-glucosidase or glucocerebrosidase (GCase), the enzyme responsible for hydrolysis of glucosyl ceramide in the lysosomes. Imino- and azasugars such as 1-deoxynojirimycin and isofagomine are strong inhibitors of the enzyme and are of interest in pharmacological chaperone therapy of the disease. Despite several crystal structures of the enzyme with the imino- and azasugars bound in the active site having been resolved, the actual acid-base chemistry of the binding is not known. In this study we show, using photoinduced electron transfer (PET), that 1-deoxynojirimycin and isofagomine derivatives are protonated by human acid β-glucosidase when bound, even if they are completely unprotonated outside the enzyme. While isofagomine derivative protonation to some degree was foreshadowed by earlier crystal structures, 1-deoxynojirimycin derivatives were not believed to act as basic amines in the enzyme. © 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.


Camilla Matassini, Julia Warren, Bo Wang, Andrea Goti, Francesca Cardona, Amelia Morrone, Mikael Bols. Imino- and Azasugar Protonation Inside Human Acid β-Glucosidase, the Enzyme that is Defective in Gaucher Disease. Angewandte Chemie (International ed. in English). 2020 Jun 22;59(26):10466-10469

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PMID: 32191378

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