Download MendeleyMolecular Basis of 1-Deoxygalactonojirimycin Arylthiourea Binding to Human alpha-Galactosidase A: Pharmacological Chaperoning Efficacy on Fabry Disease Mutants.
Yu, Y., Mena-Barragan, T., Higaki, K., Johnson, J.L., Drury, J.E., Lieberman, R.L., Nakasone, N., Ninomiya, H., Tsukimura, T., Sakuraba, H., Suzuki, Y., Nanba, E., Mellet, C.O., Garcia Fernandez, J.M., Ohno, K.(2014) ACS Chem Biol 9: 1460-1469
- PubMed: 24783948
- DOI: https://doi.org/10.1021/cb500143h
- Primary Citation of Related Structures:
4NXS - PubMed 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.
Organizational Affiliation:
Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University , Yonago 683-8503, Japan.
