Chemoproteomics and Phosphoproteomics Profiling Reveals Salvianolic Acid A as a Covalent Inhibitor of mTORC1

文献类型： 外文期刊

第一作者： Zheng, Mengmeng

作者： Zheng, Mengmeng;Zhang, Yanmei;Xu, Yao;Kang, Jingwu;Zheng, Mengmeng;Xu, Yao;Zhang, Yanmei;Han, Ying;Wu, Yingli;Kang, Jingwu

作者机构： Chinese Acad Sci, Shanghai Inst Organ Chem, Ctr Excellence Mol Synth, State Key Lab Chem Biol, Shanghai 200032, Peoples R China;Univ Chinese Acad Sci, Beijing 101408, Peoples R China;Shanghai Acad Agr Sci, Inst Agrifood Stand & Testing Technol, Shanghai 201403, Peoples R China;ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China;Shanghai Jiao Tong Univ, Shanghai Tongren Hosp, Sch Med, Key Lab Cell Differentiat & Apoptosis,Natl Minist, Shanghai 200025, Peoples R China;ShanghaiTech Univ, Sch Phys Sci & Technol, Shanghai 201210, Peoples R China

关键词： chemoproteomics; covalentinhibitors; drugtarget identification; phosphoproteomics; salvianolicacid A

期刊名称：JOURNAL OF PROTEOME RESEARCH （ 2022影响因子：4.4； 五年影响因子：4.4 ）

ISSN： 1535-3893

年卷期： 2023 年 22 卷 7 期

页码：

收录情况： SCI

摘要： Salvianolicacid A (SAA), a major active ingredient of Salvia miltiorrhizaBunge (Danshen), displays strong antiproliferative activity againstcancer cells. However, their protein targets remain unknown. Here,we deconvoluted the protein targets of SAA using chemoproteomics andphosphoproteomics. By using alkynylated SAA as a probe, we discoveredthat SAA is a covalent ligand that can modify cellular proteins viaits electrophilic & alpha;,& beta;-unsaturated ester moiety. The subsequentchemoproteomics profiling revealed that 46 proteins were covalentlymodified by SAA, including Raptor, a subunit of mTORC1 for recruitingsubstrates for mTORC1. Although gene ontology enrichment analysisof these proteins suggested that SAA displays a promiscuous proteininteraction, phosphoproteomics profiling revealed that the SAA modulatedphosphoproteins were mainly enriched in the signaling pathways ofPI3K-Akt-mTOR, which is closely related to cell growth and proliferation.This was confirmed by the biochemical assay with purified mTORC1,a Western blot assay with phospho-specific antibodies, and a cellularthermal shift assay. Our work discovered that SAA is a covalent ligandfor protein modification and mTORC1 is one of its targets. Moreover,our work demonstrated that the integrative profiling of chemoproteomicsand phosphoproteomics can be a powerful tool for target deconvolutionfor bioactive natural products.

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