Competitive and covalent inhibitors of human lysosomal retaining exoglucosidases

TY - CHAP

T1 - Competitive and covalent inhibitors of human lysosomal retaining exoglucosidases

AU - Breen, Imogen Z.

AU - Artola, Marta

AU - Wu, Liang

AU - Beenakker, Thomas

AU - Offen, Wendy A.

AU - Aerts, Johannes M. F. G.

AU - Davies, Gideon J.

AU - Overkleeft, Herman S.

PY - 2018/1/22

Y1 - 2018/1/22

N2 - 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.

AB - 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.

U2 - 10.1002/9780470015902.a0027591

DO - 10.1002/9780470015902.a0027591

M3 - Chapter

BT - eLS

ER -