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Structural basis of pharmacological chaperoning for human β-galactosidase.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2014 May 23; Vol. 289 (21), pp. 14560-8. Date of Electronic Publication: 2014 Apr 15. - Publication Year :
- 2014
-
Abstract
- GM1 gangliosidosis and Morquio B disease are autosomal recessive diseases caused by the defect in the lysosomal β-galactosidase (β-Gal), frequently related to misfolding and subsequent endoplasmic reticulum-associated degradation. Pharmacological chaperone (PC) therapy is a newly developed molecular therapeutic approach by using small molecule ligands of the mutant enzyme that are able to promote the correct folding and prevent endoplasmic reticulum-associated degradation and promote trafficking to the lysosome. In this report, we describe the enzymological properties of purified recombinant human β-Gal(WT) and two representative mutations in GM1 gangliosidosis Japanese patients, β-Gal(R201C) and β-Gal(I51T). We have also evaluated the PC effect of two competitive inhibitors of β-Gal. Moreover, we provide a detailed atomic view of the recognition mechanism of these compounds in comparison with two structurally related analogues. All compounds bind to the active site of β-Gal with the sugar-mimicking moiety making hydrogen bonds to active site residues. Moreover, the binding affinity, the enzyme selectivity, and the PC potential are strongly affected by the mono- or bicyclic structure of the core as well as the orientation, nature, and length of the exocyclic substituent. These results provide understanding on the mechanism of action of β-Gal selective chaperoning by newly developed PC compounds.<br /> (© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Subjects :
- 1-Deoxynojirimycin analogs & derivatives
1-Deoxynojirimycin chemistry
1-Deoxynojirimycin pharmacology
Catalytic Domain
Crystallography, X-Ray
Cyclohexenes chemistry
Cyclohexenes pharmacology
Enzyme Inhibitors chemistry
Enzyme Stability drug effects
Gangliosidosis, GM1 genetics
Hexosamines chemistry
Hexosamines pharmacology
Humans
Hydrogen Bonding
Hydrogen-Ion Concentration
Imino Sugars chemistry
Imino Sugars pharmacology
Inositol analogs & derivatives
Inositol chemistry
Inositol pharmacology
Kinetics
Models, Molecular
Molecular Structure
Mucopolysaccharidosis IV genetics
Mutation
Protein Structure, Tertiary
Static Electricity
Structure-Activity Relationship
beta-Galactosidase chemistry
beta-Galactosidase genetics
Enzyme Inhibitors pharmacology
Gangliosidosis, GM1 enzymology
Mucopolysaccharidosis IV enzymology
beta-Galactosidase antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 289
- Issue :
- 21
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 24737316
- Full Text :
- https://doi.org/10.1074/jbc.M113.529529