Native mass spectrometry-based metabolomics identifies metal-binding compounds
Open accessAbstract
Although metals are essential for the molecular machineries of life, systematic methods for discovering metal-small molecule complexes from biological samples are limited. Here, we describe a two-step native electrospray ionization-mass spectrometry method, in which post-column pH adjustment and metal infusion are combined with ion identity molecular networking, a rule-based data analysis workflow. This method enabled the identification of metal-binding compounds in complex samples based on defined mass (m/z) offsets of ion species with the same chromatographic profiles. As this native electrospray metabolomics approach is suited to the use of any liquid chromatography-mass spectrometry system to explore the binding of any metal, this method has the potential to become an essential strategy for elucidating metal-binding molecules in biology.
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Proof-of-concept experiments demonstrated the strategy's ability to find known siderophores from E. coli Nissle supernatant extracts and from dissolved organic matter samples from the California Current Ecosystem.
“With this set-up, proof-of-concept experiments were performed to demonstrate this strategy's ability to find known siderophores from E. coli Nissle supernatant extracts (yersiniabactin, aerobactin, HPTT-COOH) and from dissolved organic matter samples from the California Current Ecosystem (domoic acid).86”
From Connecting metabolome and phenotype: recent advances in functional metabolomics tools for the identification of bioactive natural products (2024) · cites this paper as [86]
The Results section, “Observing Siderophores in Culture Extracts,” reports identifying yersiniabactin, aerobactin, and HPTzTn-COOH in E. coli Nissle supernatant extracts. “Observing Metal-Binding Molecules in Complex Environmental Samples” reports finding domoic acid in California Current Ecosystem dissolved organic matter, but identifies it as a copper-binding molecule, not a siderophore. (LLM, conf=0.90)
Experimental — accuracy not yet measuredOnline post-column complex formation by addition of a metal binding partner has been used to study carbohydrates and siderophores.
“Online Post-column complex formation by addition of metal binding partner has been used, to study carbohydrates67 and siderophores68, respectively, which we here expand to protein targets as binding partners.”
From Native metabolomics identifies the rivulariapeptolide family of protease inhibitors (2022) · cites this paper as [68]
A modified native mass spectrometry-based set-up was used to probe for metallophores in culture supernatant extracts and complex environmental samples.
“Recently, a modified native mass spectrometry-based set-up was used to probe for metallophores in culture supernatant extracts and complex environmental samples.86”
From Connecting metabolome and phenotype: recent advances in functional metabolomics tools for the identification of bioactive natural products (2024) · cites this paper as [86]
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References 96 · Cited by 79
Research works printed but not linked: 2
- [64]Crizer DM, Xia Y. & McLuckey SA Transition metal complex cations as reagents for gas-phase transformation of multiply deprotonated polypeptides. J. Am. Soc. Mass Spectrom 20, 1718– 1722 (2011). 19535265
- [95]Wang H, & Agnes GR Kinetically Labile Equilibrium Shifts Induced by the Electrospray Process. Anal. Chem. 71, 4166– 4172 (1999). 21662847
- Authors
- Aron, A. T., Petras, D., Schmid, R., Gauglitz, J. M., Büttel, I., Antelo, L., Zhi, H., Nuccio, S.-P., Saak, C. C., Malarney, K. P., Thines, E., Dutton, R. J., Aluwihare, L. I., Raffatellu, M., & Dorrestein, P. C.
- Affiliations
- University of California San Diego (US)
- Scripps Institution of Oceanography (US)
- University of Münster (DE)
- Johannes Gutenberg University Mainz (DE)
- Chiba University (JP)
- Corresponding author
- Dorrestein, Pieter C.
- ORCID
- Venue
- Nature Chemistry
- Published
- 2021-11-18
- Volume
- 14
- Issue
- 1
- Pages
- 100-109
- ISSN
- 1755-4330 (ISSN-L)
- 1755-4349
- PMC
- PMC8959065
- OpenAlex
- W3213152569
- Cited by
- 79
- References
- 96
- Citations by year
- 2026: 15 · 2025: 21 · 2024: 18 · 2023: 11 · 2022: 13 · 2021: 1
- FWCI
- 3.93
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Chemistry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (1s10rr029121-01)
- National Institute of General Medical Sciences (P41GM103484)
- National Institute of Allergy and Infectious Diseases (R01AI114625, R56AI114625, R01AI145325, R01AI126277, R37AI126277)
- National Center for Research Resources (S10-RR029121)
- National Center for Complementary and Integrative Health (DP2AT010401)
- Topics
- Physical Sciences › Chemistry › Spectroscopy › Mass Spectrometry Techniques and Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Keywords
- native mass spectrometry, biological specimen
- MeSH terms
- Binding Sites, Chromatography, Liquid, Metals, Mass Spectrometry, Metabolomics
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