Molecular basis of 1-deoxygalactonojirimycin arylthiourea binding to human α-galactosidase a: pharmacological chaperoning efficacy on Fabry disease mutants.
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.
Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University , Yonago 683-8503, Japan.
Yi
Y
Yu
Teresa
T
Mena-Barragán
Katsumi
K
Higaki
Jennifer L
JL
Johnson
Jason E
JE
Drury
Raquel L
RL
Lieberman
Naoe
N
Nakasone
Haruaki
H
Ninomiya
Takahiro
T
Tsukimura
Hitoshi
H
Sakuraba
Yoshiyuki
Y
Suzuki
Eiji
E
Nanba
Carmen Ortiz
CO
Mellet
José M
JM
García Fernández
Kousaku
K
Ohno
D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D019556:COS Cells; D002522:Chlorocebus aethiops; D018360:Crystallography, X-Ray; D004795:Enzyme Stability / Q000187:drug effects; D000795:Fabry Disease / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D062105:Molecular Docking Simulation; D009154:Mutation; D021381:Protein Transport / Q000187:drug effects; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014281:Trihexosylceramides / Q000378:metabolism; D000519:alpha-Galactosidase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D014281:Trihexosylceramides; D017485:1-Deoxynojirimycin; C018549:globotriaosylceramide; C090092:migalastat; D000519:alpha-Galactosidase; D013890:Thiourea