Molecular basis of 1-deoxygalactonojirimycin arylthiourea binding to human -galactosidase: Pharmacological chaperoning efficacy on Fabry disease mutants.
Molecular basis of 1-deoxygalactonojirimycin arylthiourea binding to human -galactosidase: Pharmacological chaperoning efficacy on Fabry disease mutants.
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1-脱氧半乳糖野尻霉素芳基硫脲与人结合的分子基础
DOI：
10.1021/cb500143h
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Yu Y,
中科院分区：
文献类型：
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作者：
Togawa T.;Takada M.;Aizawa Y.;Tsukimura T.;Chiba Y.;Sakuraba H.;小松誠一郎，森谷昇太，車暁芳，河野範男，宮澤啓介;Akiko Okuda;森谷昇太，小松誠一郎，山﨑佳穗，車暁芳，宮澤啓介;奥田明子;Yu Y,
法布里病（Fabry disease，FD）是一种X连锁的溶酶体贮积症，由GLA基因突变引起，常导致α-半乳糖苷酶A（α-Gal A）的错义变异，由于折叠缺陷而发生过早的内质网相关降解。我们合成并表征了一个新的中性两亲性药物分子伴侣家族，即1-脱氧半乳糖基野尻霉素-芳基硫脲（DGJ-ArTs），其能够稳定α-Gal A并恢复运输。通过2.55 μ m分辨率的共晶结构证实，与酶的结合通过涉及芳基-N ′H硫脲质子和α-Gal A的催化性天冬氨酸D231的强氢键来加强。选择的候选物增强了FD细胞培养物中的α-Gal A活性并改善了神经酰胺三己糖苷（Gb 3）积累和自噬损伤。此外，它们与蛋白质稳态调节剂4-苯基丁酸协同作用，似乎是有前途的药物伴侣FD的线索。
Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in theGLAgene 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.