Accelerated transport and maturation of lysosomal α-galactosidase A in Fabry lymphoblasts by an enzyme inhibitor
Accelerated transport and maturation of lysosomal α-galactosidase A in Fabry lymphoblasts by an enzyme inhibitor
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DOI：
10.1038/4801
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发表时间：
1999-01-01
期刊：
影响因子：
82.9
通讯作者：
Suzuki, Y
中科院分区：
文献类型：
--
作者：
Fan, JQ;Ishii, S;Suzuki, Y
法布里病是一种由溶酶体 α-半乳糖苷酶 A (α-Gal A) 缺乏引起的鞘糖脂代谢紊乱，导致肾衰竭、过早心肌梗死和中风 (1,2)。目前尚无针对这种疾病的有效治疗方法。对许多 Fabry 患者体内突变酶残留活性的研究表明，其中一些突变酶的动力学特性与正常 α-Gal A 相似，但稳定性明显较差，特别是在中性 pH 条件下（参考文献 3-5）。法布里患者培养的成纤维细胞中生物合成过程延迟(6)，突变蛋白在内质网中形成聚集体：表明某些突变体中酶的缺乏主要是由于从内质网退出失败(7)，导致酶过度降解。我们在此报告，1-脱氧半乳糖野尻霉素 (DGJ) 是一种有效的 α-Gal A 竞争性抑制剂，当其给药浓度低于细胞内抑制该酶通常所需的浓度时，可有效增强法布里淋巴母细胞中的 α-Gal A 活性。 DGJ 似乎加速了突变酶的运输和成熟。给过度表达突变型 α-Gal A 的转基因小鼠口服 DGJ 显着提高了某些器官中的酶活性。我们提出了一种针对遗传代谢疾病的新分子治疗策略，即以亚抑制细胞内浓度施用竞争性抑制剂作为“化学伴侣”。
Fabry disease is a disorder of glycosphingolipid metabolism caused by deficiency of lysosomal alpha-galactosidase A (alpha-Gal A), resulting in renal failure along with premature myocardial infarction and strokes(1,2). No effective treatment of this disorder is available at present. Studies of residual activities of mutant enzymes in many Fabry patients showed that some of them had kinetic properties similar to those for normal alpha-Gal A, but were significantly less stable, especially in conditions of neutral pH (refs. 3-5). The biosynthetic processing was delayed in cultured fibroblasts of a Fabry patient(6) and the mutant protein formed an aggregate in endoplasmic reticulum: indicating that the enzyme deficiency in some mutants was mainly caused by abortive exit from the endoplasmic reticulum(7), leading to excessive degradation of the enzyme. We report here that 1-deoxy-galactonojirimycin (DGJ), a potent competitive inhibitor of alpha-Gal A, effectively enhanced alpha-Gal A activity in Fabry lymphoblasts, when administrated at concentrations lower than that usually required for intracellular inhibition of the enzyme. DGJ seemed to accelerate transport and maturation of the mutant enzyme. Oral administration of DGJ to transgenic mice overexpressing a mutant alpha-Gal A substantially elevated the enzyme activity in some organs. We propose a new molecular therapeutic strategy for genetic metabolic diseases of administering competitive inhibitors as 'chemical chaperons' at sub-inhibitory intracellular concentrations.