Structural basis of pharmacological chaperoning for human β-galactosidase.

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.

• Authors: Hironori Suzuki, Umeharu Ohto, Katsumi Higaki, Teresa Mena-Barragán, Matilde Aguilar-Moncayo, Carmen Ortiz Mellet, Eiji Nanba, Jose M Garcia Fernandez, Yoshiyuki Suzuki, Toshiyuki Shimizu
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 289 Issue 21 Pg. 14560-8 (May 23 2014) ISSN: 1083-351X [Electronic] United States
• PMID: 24737316 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Cyclohexenes
• Enzyme Inhibitors
• Hexosamines
• Imino Sugars
• N-octyl-beta-valienamine
• proto-quercitol
• 1-Deoxynojirimycin
• valienamine
• Inositol
• beta-Galactosidase
• nojirimycin

Topics

• 1-Deoxynojirimycin (analogs & derivatives, chemistry, pharmacology)
• Catalytic Domain
• Crystallography, X-Ray
• Cyclohexenes (chemistry, pharmacology)
• Enzyme Inhibitors (chemistry, pharmacology)
• Enzyme Stability (drug effects)
• Gangliosidosis, GM1 (enzymology, genetics)
• Hexosamines (chemistry, pharmacology)
• Humans
• Hydrogen Bonding
• Hydrogen-Ion Concentration
• Imino Sugars (chemistry, pharmacology)
• Inositol (analogs & derivatives, chemistry, pharmacology)
• Kinetics
• Models, Molecular
• Molecular Structure
• Mucopolysaccharidosis IV (enzymology, genetics)
• Mutation
• Protein Structure, Tertiary
• Static Electricity
• Structure-Activity Relationship
• beta-Galactosidase (antagonists & inhibitors, chemistry, genetics)