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ShanghaiTech University Knowledge Management System
| Discovery of AHCY as an Off-Target of Doxorubicin by Integrative Analysis of Photoaffinity Labeling Chemoproteomics and Untargeted Metabolomics | |
| 2022-11-01 | |
| 发表期刊 | ANALYTICAL CHEMISTRY (IF:6.7[JCR-2023],6.5[5-Year]) |
| ISSN | 0003-2700 |
| EISSN | 1520-6882 |
| 发表状态 | 已发表 |
| DOI | 10.1021/acs.analchem.2c03377 |
| 摘要 | Target identification is critically important for understanding the mechanism of action of drugs. Here, we reported a new strategy for deconvolution of drug targets (or off-targets) with photoaffinity labeling chemoproteomics in combina-tion with untargeted metabolomics by using doxorubicin (DOX) as a model. The DOX-derived photoaffinity probes were prepared and applied to capture DOX-interacting proteins in living cells. The captured DOX-interacting proteins were then identified by label-free quantitative proteomics. Totally, 151 significant proteins were identified with high confidence (fold change >4, p-value < 0.005). The gene ontology enrichment analysis suggested that the proteins were mainly involved in carbon metabolism, citrate cycle, fatty acid metabolism, and metabolic pathways. Therefore, untargeted metabolomics was applied to quantify the significantly altered metabolites in cells upon drug treatment. The pathway enrichment analysis suggested that DOX mainly interrupted with the processes of pyrimidine and purine metabolism, carbon metabolism, methionine metabolism, and phosphatidylcholine biosynthesis. Integrative analysis of chemoproteomics and metabolomics indicated that adenosylhomocysteinase (AHCY) is a new target (off-target) of DOX leading to the accumulation of S-adenosyl homocysteine. This deduced DOX target was confirmed by the cellular thermal shift assay, affinity competitive pull-down assay, biochemical assay, and siRNA knock down experiments. Our result suggested that AHCY is the uncovered off-target of DOX. |
| URL | 查看原文 |
| 收录类别 | SCI |
| 语种 | 英语 |
| 资助项目 | [92053101] ; [21775158] ; [XDB20020200] |
| WOS研究方向 | Chemistry |
| WOS类目 | Chemistry, Analytical |
| WOS记录号 | WOS:000891459500001 |
| 出版者 | AMER CHEMICAL SOC |
| 引用统计 | 正在获取...
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| 文献类型 | 期刊论文 |
| 条目标识符 | https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/256379 |
| 专题 | 物质科学与技术学院_博士生 物质科学与技术学院_特聘教授组_康经武组 生命科学与技术学院_公共科研平台_组学分析平台 物质科学与技术学院_硕士生 |
| 通讯作者 | Kang, Jingwu |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Organ Chem, Ctr Excellence Mol Synth, State Key Lab Bioorgan & Nat Prod Chem, Shanghai 200032, Peoples R China 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 3.ShanghaiTech Univ, Sch Phys Sci & Technol, Shanghai 200120, Peoples R China 4.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 200120, Peoples R China |
| 通讯作者单位 | 物质科学与技术学院 |
| 推荐引用方式 GB/T 7714 | Qian, Shanshan,Han, Ying,Zhang, Yue,et al. Discovery of AHCY as an Off-Target of Doxorubicin by Integrative Analysis of Photoaffinity Labeling Chemoproteomics and Untargeted Metabolomics[J]. ANALYTICAL CHEMISTRY,2022. |
| APA | Qian, Shanshan.,Han, Ying.,Zhang, Yue.,Du, Yanan.,Li, Jing.,...&Kang, Jingwu.(2022).Discovery of AHCY as an Off-Target of Doxorubicin by Integrative Analysis of Photoaffinity Labeling Chemoproteomics and Untargeted Metabolomics.ANALYTICAL CHEMISTRY. |
| MLA | Qian, Shanshan,et al."Discovery of AHCY as an Off-Target of Doxorubicin by Integrative Analysis of Photoaffinity Labeling Chemoproteomics and Untargeted Metabolomics".ANALYTICAL CHEMISTRY (2022). |
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