Imino‐ and Azasugar Protonation Inside Human Acid β‐Glucosidase, the Enzyme that is Defective in Gaucher Disease
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Imino‐ and Azasugar Protonation Inside Human Acid β‐Glucosidase, the Enzyme that is Defective in Gaucher Disease. / Matassini, Camilla; Warren, Julia; Wang, Bo; Goti, Andrea; Cardona, Francesca; Morrone, Amelia; Bols, Mikael.
I: Angewandte Chemie International Edition, Bind 59, Nr. 26, 2020, s. 10466-10469.Publikation: Bidrag til tidsskrift › Letter › Forskning › fagfællebedømt
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TY - JOUR
T1 - Imino‐ and Azasugar Protonation Inside Human Acid β‐Glucosidase, the Enzyme that is Defective in Gaucher Disease
AU - Matassini, Camilla
AU - Warren, Julia
AU - Wang, Bo
AU - Goti, Andrea
AU - Cardona, Francesca
AU - Morrone, Amelia
AU - Bols, Mikael
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
U2 - 10.1002/anie.202002850
DO - 10.1002/anie.202002850
M3 - Letter
C2 - 32191378
VL - 59
SP - 10466
EP - 10469
JO - Angewandte Chemie International Edition
JF - Angewandte Chemie International Edition
SN - 1433-7851
IS - 26
ER -
ID: 240411323