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

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.

• Authors: Yi Yu, Teresa Mena-Barragán, Katsumi Higaki, Jennifer L Johnson, Jason E Drury, Raquel L Lieberman, Naoe Nakasone, Haruaki Ninomiya, Takahiro Tsukimura, Hitoshi Sakuraba, Yoshiyuki Suzuki, Eiji Nanba, Carmen Ortiz Mellet, José M García Fernández, Kousaku Ohno
• Journal: ACS chemical biology (ACS Chem Biol) Vol. 9 Issue 7 Pg. 1460-9 (Jul 18 2014) ISSN: 1554-8937 [Electronic] United States
• PMID: 24783948 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Trihexosylceramides
• 1-Deoxynojirimycin
• globotriaosylceramide
• migalastat
• alpha-Galactosidase
• Thiourea

Topics

• 1-Deoxynojirimycin (analogs & derivatives, chemistry, pharmacology)
• Animals
• Autophagy (drug effects)
• COS Cells
• Chlorocebus aethiops
• Crystallography, X-Ray
• Enzyme Stability (drug effects)
• Fabry Disease (drug therapy, enzymology, genetics, pathology)
• Fibroblasts (drug effects, metabolism, pathology)
• Humans
• Molecular Docking Simulation
• Mutation
• Protein Transport (drug effects)
• Thiourea (analogs & derivatives, pharmacology)
• Trihexosylceramides (metabolism)
• alpha-Galactosidase (chemistry, genetics, metabolism)