Brief Communication

Identifying metabolites by integrating metabolome databases with mass spectrometry cheminformatics

Received:
Accepted:
Published online:

Abstract

Novel metabolites distinct from canonical pathways can be identified through the integration of three cheminformatics tools: BinVestigate, which queries the BinBase gas chromatography–mass spectrometry (GC-MS) metabolome database to match unknowns with biological metadata across over 110,000 samples; MS-DIAL 2.0, a software tool for chromatographic deconvolution of high-resolution GC-MS or liquid chromatography–mass spectrometry (LC-MS); and MS-FINDER 2.0, a structure-elucidation program that uses a combination of 14 metabolome databases in addition to an enzyme promiscuity library. We showcase our workflow by annotating N-methyl-uridine monophosphate (UMP), lysomonogalactosyl-monopalmitin, N-methylalanine, and two propofol derivatives.

  • Subscribe to Nature Methods for full access:

    $59

    Subscribe

Additional access options:

Already a subscriber?  Log in  now or  Register  for online access.

References

  1. 1.

    et al. Nucleic Acids Res. 44, 1202–1213 (2016).

  2. 2.

    , & Proc. Natl. Acad. Sci. USA 112, 12549–12550 (2015).

  3. 3.

    , , & Biochem. J. 425, 1–11 (2009).

  4. 4.

    & Annu. Rev. Biochem. 79, 471–505 (2010).

  5. 5.

    , & Nat. Chem. Biol. 9, 72–80 (2013).

  6. 6.

    , , , & Environ. Health Perspect. 122, 769–774 (2014).

  7. 7.

    et al. Proc. Natl. Acad. Sci. USA 106, 3698–3703 (2009).

  8. 8.

    , , , & Anal. Chem. 83, 5895–5902 (2011).

  9. 9.

    , & Curr. Opin. Chem. Biol. 36, 70–76 (2017).

  10. 10.

    et al. Metabolomics 10, 737–743 (2014).

  11. 11.

    , & In Data Integration in the Life Sciences (eds. Ludäscher, B. & Raschid, L.) 224–239 (Springer-Verlag, 2005).

  12. 12.

    et al. Anal. Chem. 81, 10038–10048 (2009).

  13. 13.

    et al. Nat. Methods 12, 523–526 (2015).

  14. 14.

    et al. Anal. Chem. 88, 7946–7958 (2016).

  15. 15.

    et al. J. Cheminform. 7, 44 (2015).

  16. 16.

    Trends Analyt. Chem. 27, 261–269 (2008).

  17. 17.

    & Mass Spectrom. Rev. (2016).

  18. 18.

    et al. Nucleic Acids Res. 44, D463–D470 (2016).

  19. 19.

    et al. Nucleic Acids Res. 41, D781–D786 (2013).

  20. 20.

    et al. Nat. Cell Biol. 17, 1523–1535 (2015).

  21. 21.

    et al. Anal. Chem. 79, 966–973 (2007).

  22. 22.

    & In Pacific Symposium on Biocomputing 169–180 (World Scientific, 2007).

  23. 23.

    et al. Plant J. 53, 691–704 (2008).

  24. 24.

    et al. Clin. Chim. Acta 460, 23–32 (2016).

  25. 25.

    Curr. Protoc. Mol. Biol. 114, 30.4.1–30.4.32 (2016).

  26. 26.

    et al. J. Biosci. Bioeng. 112, 292–298 (2011).

  27. 27.

    J. Am. Soc. Mass Spectrom. 10, 770–781 (1999).

  28. 28.

    , , & Anal. Chem. 88, 7689–7697 (2016).

  29. 29.

    , , & Rapid Commun. Mass Spectrom. 29, 1521–1529 (2015).

  30. 30.

    et al. BMC Genomics 13, 334 (2012).

  31. 31.

    , , & Mol. Cell. Proteomics 11, 973–988 (2012).

  32. 32.

    et al. Proc. Natl. Acad. Sci. USA 106, 17187–17192 (2009).

  33. 33.

    , , & Phys. Chem. Chem. Phys. 13, 15283–15290 (2011).

  34. 34.

    , , , & J. Med. Chem. 30, 2227–2231 (1987).

  35. 35.

    , & J. Med. Chem. 49, 7076–7087 (2006).

Download references

Acknowledgements

This work was supported by the US National Science Foundation (NSF)–Japan Science and Technology Agency (JST) Strategic International Collaborative Research Program (SICORP) for Japan–United States metabolomics. We appreciate funding from the US National Science Foundation (projects MCB 113944 and MCB 1611846 to O.F.), the US National Institutes of Health (U24 DK097154 to O.F.), and AMED–Core Research for Evolutionary Science and Technology (AMED-CREST) and JSPS KAKENHI (grants 15K01812, 15H05897, 15H05898, 17H03621 to M.A.).

Author information

Author notes

    • Zijuan Lai
    •  & Hiroshi Tsugawa

    These authors contributed equally to this work.

Affiliations

  1. West Coast Metabolomics Center, UC Davis, Davis, California, USA.

    • Zijuan Lai
    • , Gert Wohlgemuth
    • , Sajjan Mehta
    • , Matthew Mueller
    • , John Meissen
    • , Megan Showalter
    • , Tobias Kind
    •  & Oliver Fiehn
  2. Department of Chemistry, UC Davis, Davis, California, USA.

    • Zijuan Lai
    • , Yuxuan Zheng
    •  & Peter Beal
  3. RIKEN Center for Sustainable Resource Science, Yokohama, Japan.

    • Hiroshi Tsugawa
    •  & Masanori Arita
  4. RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

    • Hiroshi Tsugawa
  5. Reifycs Inc., Tokyo, Japan.

    • Atsushi Ogiwara
  6. Perfume Development Research Laboratory, Kao Corporation, Tokyo, Japan.

    • Kohei Takeuchi
  7. National Institute of Genetics, Mishima, Japan.

    • Masanori Arita
  8. Department of Biochemistry, King Abdulaziz University, Jeddah, Saudi Arabia.

    • Oliver Fiehn

Authors

  1. Search for Zijuan Lai in:

  2. Search for Hiroshi Tsugawa in:

  3. Search for Gert Wohlgemuth in:

  4. Search for Sajjan Mehta in:

  5. Search for Matthew Mueller in:

  6. Search for Yuxuan Zheng in:

  7. Search for Atsushi Ogiwara in:

  8. Search for John Meissen in:

  9. Search for Megan Showalter in:

  10. Search for Kohei Takeuchi in:

  11. Search for Tobias Kind in:

  12. Search for Peter Beal in:

  13. Search for Masanori Arita in:

  14. Search for Oliver Fiehn in:

Contributions

Z.L., H.T., M.A., and O.F. designed the research. G.W. and S.M. developed the BinVestigate program. H.T. developed the MS-DIAL 2.0 and MS-FINDER 2.0 programs. Z.L. performed the sample preparation, instrumental analysis, and data processing for unknown-compound identification. M.S. contributed biological and LC-MS studies for the identification of N-methyl-UMP. T.K. trained Z.L. in cheminformatics and contributed to validation of MS-FINDER. M.M. wrote the front end for BinVestigate. Z.L. and H.T. performed performance validation and program comparison for MS-DIAL 2.0 and MS-FINDER 2.0. Y.Z. and P.B. synthesized the N-methyl-UMP standard compound. A.O. improved the raw data file reader in ABF conversion. J.M., K.T., and O.F. contributed to the identification of lyso-MGMP and propofol derivatives. Z.L., H.T., M.A., and O.F. thoroughly discussed this project and wrote the manuscript.

Competing interests

A.O. is a developer in Reifycs Inc., which provides the ABF converter of mass spectral data for free at http://www.reifycs.com/AbfConverter/.

Corresponding authors

Correspondence to Masanori Arita or Oliver Fiehn.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–14

  2. 2.

    Life Sciences Reporting Summary

  3. 3.

    Supplementary Data Set 1

    Examples of mass spectral deconvolution results from different vendors' instruments obtained with MS-DIAL 2.0.(a) Leco nominal mass GC-TOF-MS. (b) Shimadzu nominal mass GCQMS. (c) Thermo Fisher accurate mass GC-QExactive MS. (d) Bruker accurate mass GC-TOF-MS.

Excel files

  1. 1.

    Supplementary Table 1

    Software comparison for MS-FINDER 2.0 versus CFM-ID, MetFrag, Molecular Structure Correlator (MSC), and MassFrontier

  2. 2.

    Supplementary Table 2

    Software comparison for MS-DIAL 2.0 versus AMDIS, AnalyzerPro, and ChromaTOF

  3. 3.

    Supplementary Table 3

    Summary of false discovery rate studies