Reactomics: Using mass spectrometry as a chemical reaction detector

Untargeted metabolomics analysis captures chemical reactions among small molecules. Common mass spectrometry-based metabolomics workflows first identify the small molecules significantly associated with the outcome of interest, then begin exploring their biochemical relationships to understand biological fate (environmental studies) or biological impact (physiological response). We suggest an alternative by which biochemical relationships can be directly retrieved through untargeted high-resolution paired mass distance (PMD) analysis without a priori knowledge of the identities of participating compounds. Retrieval is done using high resolution mass spectrometry as a chemical reaction detector, where PMDs calculated from the mass spectrometry data are linked to biochemical reactions obtained via data mining of small molecule and reaction databases, i.e. Reactomics. We demonstrate applications of reactomics including PMD network analysis, source appointment of unknown compounds, and biomarker reaction discovery as a complement to compound discovery analyses used in traditional untargeted workflows. An R implementation of reactomics analysis and the reaction/PMD databases is available as the pmd package (https://yufree.github.io/pmd/).