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Analytical Chemistry

Analytical Chemistry

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Discovery of AHCY as an Off-Target of Doxorubicin by Integrative Analysis of Photoaffinity Labeling Chemoproteomics and Untargeted Metabolomics

Published:29 November 2022 DOI: 10.1021/acs.analchem.2c03377 PMID: 36445716
Shanshan Qian, Ying Han, Yue Zhang, Yanan Du, Jing Li, Xin Yang and Jingwu Kang*, 

Abstract

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 combination 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.

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Materials
Procduct Name CAS Molecular Formula Supplier Price
Adriamycin 23214-92-8 C27H29NO11 289 suppliers Inquiry
Adriamycin 23214-92-8 C27H29NO11 289 suppliers Inquiry
Adriamycin 23214-92-8 C27H29NO11 289 suppliers Inquiry
Adriamycin 23214-92-8 C27H29NO11 289 suppliers Inquiry
Epirubicin 56420-45-2 C27H29NO11 182 suppliers Inquiry
Epirubicin 56420-45-2 C27H29NO11 182 suppliers Inquiry
Epirubicin 56420-45-2 C27H29NO11 182 suppliers Inquiry
Epirubicin 56420-45-2 C27H29NO11 182 suppliers Inquiry
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