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J Biol Chem. 2014 May 23;289(21):14560-8. doi: 10.1074/jbc.M113.529529. Epub 2014 Apr 15.

Structural basis of pharmacological chaperoning for human β-galactosidase.

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From the Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
the Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan.
the Department of Organic Chemistry, Faculty of Chemistry, University of Seville, Profesor García González 1, E-41012 Seville, Spain.
the Institute for Chemical Research (IIQ), CSIC, University of Sevilla, Americo Vespucio 49, Isla de la Cartuja, E-41092 Sevilla, Spain.
the International University of Health and Welfare Graduate School, Kita Kanemaru, Otawara, Tochigi 324-8501, Japan, and.
From the Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan, CREST, Japan Science and Technology Agency, 4-1-8 Honcho Kawaguchi, Saitama 332-0012, Japan


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.


Crystal Structure; Galactose; Glycosidases; Lysosomal Storage Disease; X-ray Crystallography

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