Identification of a novel PHGDH covalent inhibitor by chemical proteomics and phenotypic profiling.
Identification of a novel PHGDH covalent inhibitor by chemical proteomics and phenotypic profiling.
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通过化学蛋白质组学和表型分析鉴定新型 PHGDH 共价抑制剂
DOI：
10.1016/j.apsb.2021.06.008
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发表时间：
2022-01
期刊：
影响因子：
--
通讯作者：
Kong L
中科院分区：
文献类型：
--
作者：
Chen C;Zhu T;Liu X;Zhu D;Zhang Y;Wu S;Han C;Zhang H;Luo J;Kong L
丝氨酸合成途径（SSP）的第一限速酶磷酸甘油酸脱氢酶（PHGDH）在多种肿瘤中过度活跃，这导致SSP活化并促进肿瘤发生。然而，迄今为止仅发现了少数PHGDH抑制剂，尤其是PHGDH的共价抑制剂。在这里，我们确定了withangulatin A（WA），一种天然的小分子，作为一种新的共价抑制剂PHGDH。蛋白质组学分析表明，WA可直接与PHGDH结合，并抑制PHGDH的酶活性。生物层干涉法和LC-MS/MS分析进一步证明了WA与PHGDH的半胱氨酸295残基（Cys 295）的选择性共价结合。WA通过共价修饰Cys 295，阻断PHGDH的底物结合域（SBD），发挥变构效应，诱导PHGDH失活。进一步的研究表明，WA抑制PHGDH后，谷胱甘肽合成减少，细胞内活性氧（ROS）水平升高，从而抑制肿瘤增殖。本研究表明WA是一种新型的PHGDH共价抑制剂，Cys 295是PHGDH的一个新的变构调节位点，在开发以PHGDH为靶点的抗肿瘤药物方面具有巨大的潜力。WA是一种新型的磷酸甘油酸脱氢酶（PHGDH）共价变构抑制剂，可抑制丝氨酸合成途径和PHGDH过表达的结肠癌细胞增殖。
The first rate-limiting enzyme of the serine synthesis pathway (SSP), phosphoglycerate dehydrogenase (PHGDH), is hyperactive in multiple tumors, which leads to the activation of SSP and promotes tumorigenesis. However, only a few inhibitors of PHGDH have been discovered to date, especially the covalent inhibitors of PHGDH. Here, we identified withangulatin A (WA), a natural small molecule, as a novel covalent inhibitor of PHGDH. Affinity-based protein profiling identified that WA could directly bind to PHGDH and inactivate the enzyme activity of PHGDH. Biolayer interferometry and LC–MS/MS analysis further demonstrated the selective covalent binding of WA to the cysteine 295 residue (Cys295) of PHGDH. With the covalent modification of Cys295, WA blocked the substrate-binding domain (SBD) of PHGDH and exerted an allosteric effect to induce PHGDH inactivation. Further studies revealed that with the inhibition of PHGDH mediated by WA, the glutathione synthesis was decreased and intracellular levels of reactive oxygen species (ROS) were elevated, leading to the inhibition of tumor proliferation. This study indicates WA as a novel PHGDH covalent inhibitor, which identifies Cys295 as a novel allosteric regulatory site of PHGDH and holds great potential in developing anti-tumor agents for targeting PHGDH. WA is a novel covalent-allosteric inhibitor of phosphoglycerate dehydrogenase (PHGDH), and inhibits the serine synthesis pathway and proliferation of colon cancer cells with overexpression of PHGDH.
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影响因子：
7.3
作者：
Ravez S;Corbet C;Spillier Q;Dutu A;Robin AD;Mullarky E;Cantley LC;Feron O;Frédérick R
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影响因子：
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作者：
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影响因子：
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