Molecular Basis of 1-Deoxygalactonojirimycin Arylthiourea Binding to Human 伪-Galactosidase A: Pharmacological Chaperoning Efficacy on Fabry Disease Mutants
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- 作者：Yi Yu ; Teresa Mena-Barrag谩n ; 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 ; Jos茅 M. Garc铆a Fern谩ndez ; Kousaku Ohno
- 刊名：ACS Chemical Biology
- 出版年：2014
- 出版时间：July 18, 2014
- 年：2014
- 卷：9
- 期：7
- 页码：1460-1469
- 全文大小：517K
- ISSN：1554-8937
文摘
Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the GLA gene often leading to missense 伪-galactosidase A (伪-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 伪-Gal A and restoring trafficking. Binding to the enzyme is reinforced by a strong hydrogen bond involving the aryl-N鈥睭 thiourea proton and the catalytic aspartic acid acid D231 of 伪-Gal A, as confirmed by a 2.55 脜 resolution cocrystal structure. Selected candidates enhanced 伪-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.