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Native mass spectrometry-based metabolomics identifies metal-binding compounds

Nature Chemistry volume 14, pages 100–109 (2022)Cite this article

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Abstract

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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Fig. 1: Overview of the native spray small-molecule binding experiment.
Fig. 2: Post-LC metal infusion into mixtures of standards.
Fig. 3: Native spray metal metabolomics is used to identify siderophores in bacterial culture extracts.
Fig. 4: Native spray metal metabolomics is used to identify known and novel siderophores in bacterial and fungal culture extracts.
Fig. 5: Native spray metal metabolomics of DOM samples.

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Data availability

The data supporting the findings of this study are available within the paper and its Supplementary Information. All MS .raw and centroided .mzXML or .mzML files are publicly available in the Mass spectrometry Interactive Virtual Environment (MassIVE) under massive.ucsd.edu with project identifiers MSV000084237, MSV000085669, MSV000085206 (standards), MSV000084289 (cheese siderophores), MSV000082999 and MSV000084030 (fungal siderophores), MSV000083387 (E.coli Nissle siderophores), MSV000085554 (California current ecosystem phytoplankton bloom samples) and MSV000086744 (chelomics versus native metabolomics comparison). IIMN can be accessed through gnps.ucsd.edu under the following direct links: https://gnps.ucsd.edu/ProteoSAFe/status.jsp?task=79d0f380b4814ff9a720836c5570036f, https://gnps.ucsd.edu/ProteoSAFe/status.jsp?task=ad4b2665dfb744d09a9d2445f1213720, https://gnps.ucsd.edu/ProteoSAFe/status.jsp?task=5459d22126e843a3a1449f8362cd267f, http://gnps.ucsd.edu/ProteoSAFe/status.jsp?task=1c3e79f0ab984386bd468e2d163281e0, https://gnps.ucsd.edu/ProteoSAFe/index.jsp?task=196a29a94c2f4c788e204b9934ea4d9b, http://gnps.ucsd.edu/ProteoSAFe/status.jsp?task=256ba734f4334c1c90f65ffbd9141d0e, https://gnps.ucsd.edu/ProteoSAFe/status.jsp?task=042939579da64e029a8b5caef8f7f2a8.

Code availability

The modified version of MZmine 2 (2.37, corr.17.7)41,42,43 can be found at https://mzmine.github.io/iin_fbmn. GNPS44,45 can be accessed at https://gnps.ucsd.edu/ProteoSAFe/static/gnps-splash.jsp. Cytoscape63 version 3.7.1 can be accessed at https://cytoscape.org/.

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Acknowledgements

Work in the P.C.D. laboratory was supported by grants P41-GM103484 and GMS10RR029121 and the Betty and Gordon Moore Foundation (A.T.A.). D.P. was supported through the Deutsche Forschungsgemeinschaft with grant PE 2600/1. Work in the M.R. laboratory is supported by Public Health Service grants AI126277, AI114625 and AI145325, by the Chiba University–UCSD Center for Mucosal Immunology, Allergy and Vaccines, and by the UCSD Department of Pediatrics (H.Z. and S.P.N.). M.R. also holds an Investigator in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund. Work in the R.J.D. laboratory is supported by NIH grant 1 DP2 AT010401-01 (K.P.M. and C.C.S.). We also thank A. Jarmusch and S. McLuckey for helpful discussions and B. Duggan for helpful discussions and assistance with NMR experiments.

Author information

Author notes

  1. Daniel Petras

    Present address: CMFI Cluster of Excellence, Interfaculty Institute of Microbiology and Medicine, University of Tübingen, Tübingen, Germany

  2. Julia M. Gauglitz

    Present address: Sapient Bioanalytics, La Jolla, CA, USA

  3. These authors contributed equally: Allegra T. Aron, Daniel Petras.

Authors and Affiliations

  1. Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA

    Allegra T. Aron, Daniel Petras, Robin Schmid, Julia M. Gauglitz & Pieter C. Dorrestein

  2. Collaborative Mass Spectrometry Innovation Center, University of California, San Diego, La Jolla, CA, USA

    Allegra T. Aron, Daniel Petras & Julia M. Gauglitz

  3. Scripps Institution of Oceanography, University of California, San Diego, La Jolla, CA, USA

    Daniel Petras, Lihini I. Aluwihare & Pieter C. Dorrestein

  4. Institute of Inorganic and Analytical Chemistry, University of Münster, Münster, Germany

    Robin Schmid

  5. Institute of Molecular Physiology, Microbiology and Wine Research, Johannes Gutenberg University Mainz, Mainz, Germany

    Isabell Büttel & Eckhard Thines

  6. Institute of Biotechnology and Drug Research (IBWF gGmbH), Johannes Gutenberg University Mainz, Mainz, Germany

    Luis Antelo & Eckhard Thines

  7. Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, University of California San Diego, La Jolla, CA, USA

    Hui Zhi, Sean-Paul Nuccio & Manuela Raffatellu

  8. Division of Biological Sciences, University of California, San Diego, La Jolla, CA, USA

    Christina C. Saak, Kien P. Malarney & Rachel J. Dutton

  9. Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA, USA

    Rachel J. Dutton, Manuela Raffatellu & Pieter C. Dorrestein

  10. Chiba University-University of California San Diego Center for Mucosal Immunology, Allergy, and Vaccines (CU-UCSD cMAV), La Jolla, CA, USA

    Manuela Raffatellu

Authors
  1. Allegra T. Aron
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  2. Daniel Petras
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  3. Robin Schmid
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  4. Julia M. Gauglitz
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  5. Isabell Büttel
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  6. Luis Antelo
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  7. Hui Zhi
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  8. Sean-Paul Nuccio
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  9. Christina C. Saak
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  10. Kien P. Malarney
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  11. Eckhard Thines
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  12. Rachel J. Dutton
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  13. Lihini I. Aluwihare
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  14. Manuela Raffatellu
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  15. Pieter C. Dorrestein
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Contributions

A.T.A., D.P., R.S. and P.C.D. developed the concept. D.P., J.M.G., I.B., L.A., E.T., H.Z., S.P.N., C.C.S., K.P.M., R.J.D. and M.R. cultured organisms and prepared samples. A.T.A., D.P. and J.M.G. ran MS experiments. R.S. wrote code and provided feedback. A.T.A. and D.P. analysed the data. E.T., R.J.D., L.I.A., M.R. and P.C.D. provided supervision and materials. A.T.A., D.P. and P.C.D. wrote the manuscript. All authors edited and approved the manuscript.

Corresponding author

Correspondence to Pieter C. Dorrestein.

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Competing interests

P.C.D. is a scientific adviser to Sirenas, Galileo and Cybele, and co-founder and scientific advisor to Ometa and Enveda with approval by the University of California, San Diego. M.R. is also on the scientific advisory board of Sirenas.

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Peer review information Nature Chemistry thanks Corey Broeckling and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Aron, A.T., Petras, D., Schmid, R. et al. Native mass spectrometry-based metabolomics identifies metal-binding compounds. Nat. Chem. 14, 100–109 (2022). https://doi.org/10.1038/s41557-021-00803-1

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