Identification of peroxiredoxin 6 as a direct target of withangulatin A by quantitative chemical proteomics in non-small cell lung cancer.
Identification of peroxiredoxin 6 as a direct target of withangulatin A by quantitative chemical proteomics in non-small cell lung cancer.
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通过定量化学蛋白质组学鉴定过氧化还原蛋白 6 作为非小细胞肺癌中 withangulin A 的直接靶标
DOI：
10.1016/j.redox.2021.102130
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发表时间：
2021-10
期刊：
影响因子：
11.4
通讯作者：
Luo J
中科院分区：
文献类型：
--
作者：
Chen C;Gong L;Liu X;Zhu T;Zhou W;Kong L;Luo J
过氧化物氧还蛋白6（Peroxiredoxin 6，PRDX 6）是一种具有谷胱甘肽过氧化物酶（glutathione peroxidase，GPx）活性和钙非依赖性磷脂酶A2（Ca 2 + independent phospholipase A2，iPLA 2）活性的双功能酶，在多种肿瘤细胞中表达量较高，导致抗氧化能力增强，促进肿瘤发生。然而，迄今为止仅发现了少数PRDX 6抑制剂，尤其是PRDX 6的共价抑制剂。在这里，我们首先确定了Withangulatin A（WA），一种天然的小分子，作为一种新的共价抑制剂PRDX 6。SILAC-ABPP鉴定WA可直接与PRDX 6结合，并通过α，β-不饱和酮部分抑制PRDX 6的酶活性。此外，WA还促进了ROS的产生，抑制了GPx和iPLA 2的活性。然而，具有减少的α，β-不饱和酮部分的WA-1对GPx和iPLA 2活性没有显著抑制。生物膜干涉法和LC-MS/MS分析进一步证明了WA与PRDX 6的半胱氨酸47残基（Cys 47）的选择性共价结合，而Cys 47的突变阻断了WA与PRDX 6的结合。值得注意的是，WA介导的细胞毒性和GPx和iPLA 2活性的抑制几乎被PRDX 6的缺陷所消除。因此，本研究表明WA是一种新型PRDX 6共价抑制剂，它可以与PRDX 6的Cys 47共价结合，在开发针对PRDX 6的抗肿瘤药物方面具有很大的潜力。Withangulatin A是一种新型的PRDX 6共价抑制剂。Withangulatin A抑制PRDX 6的活性，增加ROS的产生。Withangulatin A抑制GPx和iPLA 2活性。Withangulatin A选择性共价结合PRDX 6的Cys 47。Withangulatin A介导的细胞毒性和ROS的产生依赖于PRDX 6。
Peroxiredoxin 6 (PRDX6), as a bifunctional enzyme with glutathione peroxidase activity (GPx) and Ca2+-independent phospholipase A2 (iPLA2) activity, has a higher expression in various cancer cells, which leads to the increase of antioxidant properties and promotes tumorigenesis. However, only a few inhibitors of PRDX6 have been discovered to date, especially the covalent inhibitors of PRDX6. Here, we firstly identified Withangulatin A (WA), a natural small molecule, as a novel covalent inhibitor of PRDX6. SILAC-ABPP identified that WA could directly bind to PRDX6 and inactivate the enzyme activity of PRDX6 by the α, β-unsaturated ketone moiety. Moreover, WA also facilitated the generation of ROS, and inhibited the GPx and iPLA2 activities. However, WA-1, with a reduced α, β-unsaturated ketone moiety, had no significant inhibition of the GPx and iPLA2 activities. Biolayer interferometry and LC-MS/MS analysis further demonstrated the selectively covalent binding of WA to the cysteine 47 residue (Cys47) of PRDX6, while mutation of Cys47 blocked the binding of WA to PRDX6. Notably, WA-mediated cytotoxicity and inhibition of the GPx and iPLA2 activities were almost abolished by the deficiency of PRDX6. Therefore, this study indicates that WA is a novel PRDX6 covalent inhibitor, which could covalently bind to the Cys47 of PRDX6 and holds great potential in developing anti-tumor agents for targeting PRDX6. Withangulatin A is a novel covalent inhibitor of PRDX6. Withangulatin A inhibits the activity of PRDX6 and increased the generation of ROS. Withangulatin A inhibits the GPx and iPLA2 activities. Withangulatin A selective covalently binds to the Cys47 of PRDX6. Withangulatin A-mediated cytotoxicity and generation of ROS are dependent on PRDX6.
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影响因子：
3.9
作者：
Manevich Y;Shuvaeva T;Dodia C;Kazi A;Feinstein SI;Fisher AB
通讯作者：
Fisher AB
影响因子：
15
作者：
Kambe T;Correia BE;Niphakis MJ;Cravatt BF
通讯作者：
Cravatt BF
影响因子：
7.4
作者：
Devarajan A;Rajasekaran NS;Valburg C;Ganapathy E;Bindra S;Freije WA
通讯作者：
Freije WA
影响因子：
--
作者：
Arriga, Roberto;Pacifici, Francesca;Lauro, Davide
通讯作者：
Lauro, Davide
鉴定过氧蛋白6在乳腺癌进展中的功能作用。
DOI：
10.1186/bcr1789
发表时间：
2007
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Chang XZ;Li DQ;Hou YF;Wu J;Lu JS;Di GH;Jin W;Ou ZL;Shen ZZ;Shao ZM
通讯作者：
Shao ZM