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Native mass spectrometry-based metabolomics identifies metal-binding compounds

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.

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.

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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.

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Correspondence to Pieter C. Dorrestein.

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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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