Charting the Undiscovered Metabolome with Synthetic Multiplexing.
| Title: | Charting the Undiscovered Metabolome with Synthetic Multiplexing. |
|---|---|
| Authors: | Patan A; Xing S; Charron-Lamoureux V; Hu Z; Deleray V; Agongo J; El Abiead Y; Mannochio-Russo H; Mohanty I; Gouda H; Zemlin J; Rajkumar P; Lee C; Leanos D; Weimann N; Tsuda W; Giddings S; Bui T; Kvitne KE; Zhao HN; Zuffa S; Nguyen V; Andrade A; Gonçalves Nunes WD; Caraballo-Rodríguez AM; Caetano David L; Carver J; Bandeira N; Wang M; Burnett LA; Siegel D; Dorrestein PC |
| Source: | BioRxiv : the preprint server for biology [bioRxiv] 2025 Nov 19. Date of Electronic Publication: 2025 Nov 19. |
| Publication Type: | Journal Article; Preprint |
| Language: | English |
| Journal Info: | Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet ISSN: 2692-8205 (Electronic) Linking ISSN: 26928205 NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| Abstract: | In untargeted metabolomics, reference MS/MS libraries are essential for structural annotation, yet currently explain only 6.9% of the more than 1.7 billion MS/MS spectra in public repositories. We hypothesized that many unannotated features arise from simple, biologically plausible transformations of endogenous and exposure-derived compounds. To test this, we created a reference resource by synthesizing over 100,000 compounds using multiplexed reactions that mimic such biochemical transformations. 91% of the compounds synthesized are absent from existing structural databases. Through improvements in the construction of the computational infrastructure that enables pan repository-scale MS/MS comparisons, searching this biologically inspired MS/MS library increased the overall reference-based match rate by 17.4%, yielding over 60 million new matches and raising the global pan-repository MS/MS annotation rate to 8.1%. By facilitating structural hypotheses for previously uncharacterized MS/MS data, this framework expands the accessible detectable biochemical landscape across human, animal, plant, and microbial systems, revealing previously undescribed metabolites such as ibuprofen-carnitine and 5-ASA-phenylpropionic acid conjugates arising from drug-host and host-microbiome co-metabolism. |
| Entry Date(s): | Date Created: 20251203 Date Completed: 20251203 Latest Revision: 20251203 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC12667992 |
| DOI: | 10.1101/2025.11.18.689170 |
| PMID: | 41332743 |
| Database: | MEDLINE |
Journal Article; Preprint