|Title||Molecular basis of 1-deoxygalactonojirimycin arylthiourea binding to human α-galactosidase a: pharmacological chaperoning efficacy on Fabry disease mutants.|
|Publication Type||Journal Article|
|Year of Publication||2014|
|Authors||Yu, 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|
|Journal||ACS Chem Biol|
|Date Published||2014 Jul 18|
|Keywords||1-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|
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.
|Alternate Journal||ACS Chem. Biol.|
Molecular basis of 1-deoxygalactonojirimycin arylthiourea binding to human α-galactosidase a: pharmacological chaperoning efficacy on Fabry disease mutants.
Submitted by enguyen7 on December 30, 2015 - 10:55am