Molecular basis of 1-deoxygalactonojirimycin arylthiourea binding to human α-galactosidase a: pharmacological chaperoning efficacy on Fabry disease mutants.

TitleMolecular basis of 1-deoxygalactonojirimycin arylthiourea binding to human α-galactosidase a: pharmacological chaperoning efficacy on Fabry disease mutants.
Publication TypeJournal Article
Year of Publication2014
AuthorsYu, Y, Mena-Barragán, T, Higaki, K, Johnson, JL, Drury, JE, Lieberman, RL, Nakasone, N, Ninomiya, H, Tsukimura, T, Sakuraba, H, Suzuki, Y, Nanba, E, Mellet, COrtiz, Fernández, JMGarcía, Ohno, K
JournalACS Chem Biol
Volume9
Issue7
Pagination1460-9
Date Published2014 Jul 18
ISSN1554-8937
Keywords1-Deoxynojirimycin, alpha-Galactosidase, Animals, Autophagy, Cercopithecus aethiops, COS Cells, Crystallography, X-Ray, Enzyme Stability, Fabry Disease, Fibroblasts, Humans, Molecular Docking Simulation, Mutation, Protein Transport, Thiourea, Trihexosylceramides
Abstract

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the GLA gene often leading to missense α-galactosidase A (α-Gal A) variants that undergo premature endoplasmic reticulum-associated degradation due to folding defects. We have synthesized and characterized a new family of neutral amphiphilic pharmacological chaperones, namely 1-deoxygalactonojirimycin-arylthioureas (DGJ-ArTs), capable of stabilizing α-Gal A and restoring trafficking. Binding to the enzyme is reinforced by a strong hydrogen bond involving the aryl-N'H thiourea proton and the catalytic aspartic acid acid D231 of α-Gal A, as confirmed by a 2.55 Å resolution cocrystal structure. Selected candidates enhanced α-Gal A activity and ameliorate globotriaosylceramide (Gb3) accumulation and autophagy impairments in FD cell cultures. Moreover, they acted synergistically with the proteostasis regulator 4-phenylbutyric acid, appearing to be promising leads as pharmacological chaperones for FD.

DOI10.1021/cb500143h
Alternate JournalACS Chem. Biol.
PubMed ID24783948