Correcting glucose-6-phosphate dehydrogenase deficiency with a small-molecule activator.
Correcting glucose-6-phosphate dehydrogenase deficiency with a small-molecule activator.
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DOI：
10.1038/s41467-018-06447-z
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发表时间：
2018-10-02
影响因子：
16.6
通讯作者：
Mochly-Rosen D
中科院分区：
文献类型：
--
作者：
Hwang S;Mruk K;Rahighi S;Raub AG;Chen CH;Dorn LE;Horikoshi N;Wakatsuki S;Chen JK;Mochly-Rosen D
葡萄糖-6-磷酸脱氢酶（G6 PD）缺乏症是最常见的人类遗传酶病之一，由超过160种不同的点突变引起，并且导致许多与氧化应激相关的急性和慢性疾病的严重程度，包括溶血性贫血和胆红素诱导的神经损伤，特别是在新生儿中。由于没有药物可用于治疗G6 PD缺乏症，在这里，我们试图确定一个小分子，纠正it. Crystallographic研究和诱变分析确定一个常见的突变体（广州，R459 L）的结构和功能缺陷。使用高通量筛选，我们随后确定AG 1，一个小分子，增加野生型，广州突变体和其他几个常见的G6 PD突变体的活性。AG 1降低细胞和斑马鱼的氧化应激。此外，AG 1降低氯喹或二酰胺诱导的人红细胞氧化应激。我们的研究表明，AG 1可能是一种先导药物，可能会减轻与G6 PD缺乏相关的挑战。葡萄糖-6-磷酸脱氢酶（G6 PD）缺乏对氧化应激的保护不足，导致多种人类病理学。在这里，作者确定了一种小分子，可以增加突变型G6 PD的活性和/或稳定性，并表明它可以减少斑马鱼的氧化应激和分离的人红细胞的溶血。
Glucose-6-phosphate dehydrogenase (G6PD) deficiency, one of the most common human genetic enzymopathies, is caused by over 160 different point mutations and contributes to the severity of many acute and chronic diseases associated with oxidative stress, including hemolytic anemia and bilirubin-induced neurological damage particularly in newborns. As no medications are available to treat G6PD deficiency, here we seek to identify a small molecule that corrects it. Crystallographic study and mutagenesis analysis identify the structural and functional defect of one common mutant (Canton, R459L). Using high-throughput screening, we subsequently identify AG1, a small molecule that increases the activity of the wild-type, the Canton mutant and several other common G6PD mutants. AG1 reduces oxidative stress in cells and zebrafish. Furthermore, AG1 decreases chloroquine- or diamide-induced oxidative stress in human erythrocytes. Our study suggests that a pharmacological agent, of which AG1 may be a lead, will likely alleviate the challenges associated with G6PD deficiency. Glucose-6-phosphate dehydrogenase (G6PD) deficiency provides insufficient protection from oxidative stress, contributing to diverse human pathologies. Here, the authors identify a small molecule that increases the activity and/or stability of mutant G6PD and show that it reduces oxidative stress in zebrafish and hemolysis in isolated human erythrocytes.
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DOI：
10.1107/s090744491003982x
发表时间：
2011-04
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Evans PR
通讯作者：
Evans PR
DOI：
10.1107/s0907444905036693
发表时间：
2006-01-01
影响因子：
2.2
作者：
Evans, P
通讯作者：
Evans, P
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
2.7
作者：
Hebeisen, Paul;Kuhn, Bernd;Ruf, Armin
通讯作者：
Ruf, Armin
影响因子：
2.1
作者：
Cunningham AD;Hwang S;Mochly-Rosen D
通讯作者：
Mochly-Rosen D