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Imino‐ and Azasugar Protonation Inside Human Acid β‐Glucosidase, the Enzyme that is Defective in Gaucher Disease
Author(s) -
Matassini Camilla,
Warren Julia,
Wang Bo,
Goti Andrea,
Cardona Francesca,
Morrone Amelia,
Bols Mikael
Publication year - 2020
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.202002850
Subject(s) - protonation , enzyme , chemistry , glucocerebrosidase , stereochemistry , hydrolase , gaucher's disease , hydrolysis , biochemistry , disease , organic chemistry , medicine , pathology , ion
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.