Discovery and Visualization of Uncharacterized Drug-Protein Adducts Using Mass Spectrometry.
seattle; isb; washington; genomics; Algorithms; DNA Adducts; Mass Spectrometry; Proteins; Proteomics; Software
Drugs are often metabolized to reactive intermediates that form protein adducts. Adducts can inhibit protein activity, elicit immune responses, and cause life-threatening adverse drug reactions. The masses of reactive metabolites are frequently unknown, rendering traditional mass spectrometry-based proteomics approaches incapable of adduct identification. Here, we present Magnum, an open-mass search algorithm optimized for adduct identification, and Limelight, a web-based data processing package for analysis and visualization of data from all existing algorithms. Limelight incorporates tools for sample comparisons and xenobiotic-adduct discovery. We validate our tools with three drug/protein combinations and apply our label-free workflow to identify novel xenobiotic-protein adducts in CYP3A4. Our new methods and software enable accurate identification of xenobiotic-protein adducts with no prior knowledge of adduct masses or protein targets. Magnum outperforms existing label-free tools in xenobiotic-protein adduct discovery, while Limelight fulfills a major need in the rapidly developing field of open-mass searching, which until now lacked comprehensive data visualization tools.
Institute for Systems Biology
Riffle, Michael; Hoopmann, Michael R; Jaschob, Daniel; Zhong, Guo; Moritz, Robert L; MacCoss, Michael J; Davis, Trisha N; Isoherranen, Nina; and Zelter, Alex, "Discovery and Visualization of Uncharacterized Drug-Protein Adducts Using Mass Spectrometry." (2022). Articles, Abstracts, and Reports. 5894.