An Amphiphilic Selenide Catalyst Behaves Like a Hybrid Mimic of Protein Disulfide Isomerase and Glutathione Peroxidase 7
An Amphiphilic Selenide Catalyst Behaves Like a Hybrid Mimic of Protein Disulfide Isomerase and Glutathione Peroxidase 7
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DOI：
10.1002/asia.201402726
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发表时间：
2014-12-01
影响因子：
4.1
通讯作者：
Iwaoka, Michio
中科院分区：
文献类型：
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作者：
Arai, Kenta;Moriai, Kenji;Iwaoka, Michio
蛋白质二硫键异构酶(PDI)和谷胱甘肽过氧化物酶7(GPx7)协同促进内质网含二硫键(SS)蛋白质的氧化折叠，它们分别通过SS的形成和SS的异构化以及通过催化还原的PDI与H_2O_2的再氧化来识别新生蛋白质而将其转化为天然折叠。本研究设计了新型长链烷基两亲性硒化合物作为PDI和GPx7的杂化模拟物，并将其应用于还原蛋清溶菌酶(HEL-R)的复性。在pH为4的条件下，在硒催化剂和H_2O_2存在下，HEL-R和谷胱甘肽(GSH)竞争生成SS。结果表明，两亲性硒化合物能够优先催化HEL-R生成SS，这可能是由于蛋白质和催化剂之间的疏水作用所致。相比之下，简单的水溶性硒化合物没有表现出这样的行为。此外，在SS形成后，当溶液的pH调节到8.5时，存活的GSH促进了错误折叠的HEL的SS异构化，恢复了天然的SS键。因此，本文设计的两亲性硒化合物可以模拟PDI-GPx7系统的功能。水溶性硒和长链烷基团的结合将是设计蛋白质错误折叠疾病和抗氧化治疗药物的有用主题。
Protein disulfide isomerase (PDI) and glutathione peroxidase 7 (GPx7) cooperatively promote the oxidative folding of disulfide (SS)-containing proteins in endoplasmic reticulum by recognizing the nascent proteins to convert them into the native folds by means of SS formation and SS isomerization and by catalyzing reoxidation of reduced PDI with H2O2, respectively. In this study, new amphiphilic selenides with a long-chain alkyl group were designed as hybrid mimics of PDI and GPx7 and were applied to the refolding of reduced hen egg-white lysozyme (HEL-R). Competitive SS formation at pH4 using HEL-R and glutathione (GSH) in the presence of the selenide catalyst and H2O2 showed that the amphiphilic selenides can preferentially catalyze SS formation of HEL-R, probably on account of hydrophobic interactions between the protein and the catalyst. In contrast, simple water-soluble selenides did not exhibit such behavior. In addition, when the pH of the solution was adjusted to 8.5 after the SS formation, surviving GSH promoted the SS isomerization of misfolded HEL to recover the native SS linkages. Thus, the amphiphilic selenides designed here could mimic the function of the PDI-GPx7 system. The combination of a water-soluble selenide and a long-chain alkyl group would be a useful motif in designing medicines for both protein misfolding diseases and antioxidant therapy.