Comprehensive Profiling of Rapamycin Interacting Proteins with Multiple Mass Spectrometry-Based Omics Techniques.
Comprehensive Profiling of Rapamycin Interacting Proteins with Multiple Mass Spectrometry-Based Omics Techniques.
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DOI：
10.1021/acs.analchem.3c00867
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发表时间：
2023-05
影响因子：
7.4
通讯作者：
Yao Xu;Mengmeng Zheng;L. Gong;Guizhen Liu;S. Qian;Ying Han;Jingwu Kang
中科院分区：
文献类型：
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作者：
Yao Xu;Mengmeng Zheng;L. Gong;Guizhen Liu;S. Qian;Ying Han;Jingwu Kang
分析药物-蛋白质相互作用对于理解药物的作用机制和预测可能的不良副作用至关重要。然而，全面分析药物-蛋白质相互作用仍然是一个挑战。为了解决这个问题，我们提出了一种策略，整合多个质谱为基础的组学分析，提供全球药物-蛋白质相互作用，包括物理相互作用和功能相互作用，与雷帕霉素（Rap）作为一个模型。化学蛋白质组学分析揭示了47种Rap结合蛋白，包括具有高置信度的已知靶蛋白FKBP 12。Gen Ontology富集分析表明，Rap结合蛋白涉及几个重要的细胞过程，如DNA复制、免疫、自噬、程序性细胞死亡、衰老、转录调节、囊泡介导的转运、膜组织以及碳水化合物和核碱基代谢过程。磷酸化蛋白质组学分析揭示了255个下调和150个上调的磷酸化蛋白响应Rap刺激;它们主要涉及PI 3 K-Akt-mTORC 1信号传导轴。非靶向代谢组学分析揭示了22种下调的代谢物和75种上调的代谢物响应Rap刺激;它们主要与嘧啶和嘌呤的合成过程相关。整合的多组学数据分析提供了对药物-蛋白质相互作用的深入了解，并揭示了Rap复杂的作用机制。
Profiling drug-protein interactions is critical for understanding a drug's mechanism of action and predicting the possible adverse side effects. However, to comprehensively profile drug-protein interactions remains a challenge. To address this issue, we proposed a strategy that integrates multiple mass spectrometry-based omics analysis to provided global drug-protein interactions, including physical interactions and functional interactions, with rapamycin (Rap) as a model. Chemoproteomics profiling reveals 47 Rap binding proteins including the known target protein FKBP12 with high confidence. Gen Ontology enrichment analysis suggested that the Rap binding proteins are implicated in several important cellular processes, such as DNA replication, immunity, autophagy, programmed cell death, aging, transcription modulation, vesicle-mediated transport, membrane organization, and carbohydrate and nucleobase metabolic processes. The phosphoproteomics profiling revealed 255 down-regulated and 150 up-regulated phosphoproteins responding to Rap stimulation; they mainly involve the PI3K-Akt-mTORC1 signaling axis. Untargeted metabolomic profiling revealed 22 down-regulated metabolites and 75 up-regulated metabolites responding to Rap stimulation; they are mainly associated with the synthesis processes of pyrimidine and purine. The integrative multiomics data analysis provides deep insight into the drug-protein interactions and reveals Rap's complicated mechanism of action.