Skip to main content
SpringerLink
Log in

Tools for Enhanced NMR-Based Metabolomics Analysis

  • Protocol
  • First Online:
NMR-Based Metabolomics

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2037))

Abstract

Metabolomics is the study of profiles of small molecules in biological fluids, cells, or organs. These profiles can be thought of as the “fingerprints” left behind from chemical processes occurring in biological systems. Because of its potential for groundbreaking applications in disease diagnostics, biomarker discovery, and systems biology, metabolomics has emerged as a rapidly growing area of research. Metabolomics investigations often, but not always, involve the identification and quantification of endogenous and exogenous metabolites in biological samples. Software tools and databases play a crucial role in advancing the rigor, robustness, reproducibility, and validation of these studies. Specifically, the establishment of a robust library of spectral signatures with unique compound descriptors and atom identities plays a key role in profiling studies based on data from nuclear magnetic resonance (NMR) spectroscopy. Here, we discuss developments leading to a rigorous basis for unique identification of compounds, reproducible numbering of atoms, the compact representation of NMR spectra of metabolites and small molecules, tools for improved compound identification, quantification and visualization, and approaches toward the goal of rigorous analysis of metabolomics data.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Misra BB (2018) New tools and resources in metabolomics: 2016-2017. Electrophoresis 39(7):909–923

    Article  CAS  Google Scholar 

  2. Misra BB, Mohapatra S (2018) Tools and resources for metabolomics research community: A 2017–2018 update. Electrophoresis. doi: https://doi.org/10.1002/elps.201800428. [Epub ahead of print]

    Article  Google Scholar 

  3. Halabalaki M, Vougogiannopoulou K, Mikros E, Skaltsounis AL (2014) Recent advances and new strategies in the NMR-based identification of natural products. Curr Opin Biotechnol 25:1–7

    Article  CAS  Google Scholar 

  4. Ravanbakhsh S, Liu P, Bjorndahl TC, Mandal R, Grant JR, Wilson M et al (2015) Accurate, fully-automated NMR spectral profiling for metabolomics. PLoS One 10(5):e0124219

    Article  Google Scholar 

  5. Clarke CJ, Haselden JN (2008) Metabolic profiling as a tool for understanding mechanisms of toxicity. Toxicol Pathol 36(1):140–147

    Article  CAS  Google Scholar 

  6. Zhang S, Liu L, Steffen D, Ye T, Raftery D (2012) Metabolic profiling of gender: headspace-SPME/GC–MS and 1H NMR analysis of urine. Metabolomics 8(2):323–334

    Article  Google Scholar 

  7. Beckonert O, Keun HC, Ebbels TM, Bundy J, Holmes E, Lindon JC et al (2007) Metabolic profiling, metabolomic and metabonomic procedures for NMR spectroscopy of urine, plasma, serum and tissue extracts. Nat Protoc 2(11):2692–2703

    Article  CAS  Google Scholar 

  8. Jupin M, Michiels PJ, Girard FC, Spraul M, Wijmenga SS (2014) NMR metabolomics profiling of blood plasma mimics shows that medium- and long-chain fatty acids differently release metabolites from human serum albumin. J Magn Reson 239:34–43

    Article  CAS  Google Scholar 

  9. Larive CK, Barding GA, Dinges MM (2015) NMR spectroscopy for metabolomics and metabolic profiling. Anal Chem 87(1):133–146

    Article  CAS  Google Scholar 

  10. Elmsjo A, Rosqvist F, Engskog MK, Haglof J, Kullberg J, Iggman D et al (2015) NMR-based metabolic profiling in healthy individuals overfed different types of fat: links to changes in liver fat accumulation and lean tissue mass. Nutr Diabetes 5:e182

    Article  CAS  Google Scholar 

  11. Palma M, Hernandez-Castellano LE, Castro N, Arguello A, Capote J, Matzapetakis M et al (2016) NMR-metabolomics profiling of mammary gland secretory tissue and milk serum in two goat breeds with different levels of tolerance to seasonal weight loss. Mol BioSyst 12(7):2094–2107

    Article  CAS  Google Scholar 

  12. Vermathen M, Paul LEH, Diserens G, Vermathen P, Furrer J (2015) 1H HR-MAS NMR based metabolic profiling of cells in response to treatment with a Hexacationic ruthenium Metallaprism as potential anticancer drug. PLoS One 10(5):e0128478

    Article  Google Scholar 

  13. Whigham LD, Butz DE, Dashti H, Tonelli M, Johnson LK, Cook ME et al (2014) Metabolic evidence of diminished lipid oxidation in women with polycystic ovary syndrome. Curr Metabolomics 2(4):269–278

    Article  Google Scholar 

  14. Bingol K (2018) Recent advances in targeted and untargeted metabolomics by NMR and MS/NMR methods. High Throughput 7(2):E9. https://doi.org/10.3390/ht7020009

    Article  CAS  PubMed  Google Scholar 

  15. Worley B, Powers R (2014) MVAPACK: a complete data handling package for NMR metabolomics. ACS Chem Biol 9(5):1138–1144

    Article  CAS  Google Scholar 

  16. Vignoli A, Ghini V, Meoni G, Licari C, Takis PG, Tenori L et al (2018) High-throughput metabolomics by 1D NMR. Angew Chem Int Ed Engl. https://doi.org/10.1002/anie.201804736e. [Epub ahead of print]

  17. Napolitano JG, Lankin DC, McAlpine JB, Niemitz M, Korhonen S-P, Chen S-N et al (2013) Proton fingerprints portray molecular structures: enhanced description of the 1H NMR spectra of small molecules. J Org Chem 78(19):9963–9968

    Article  CAS  Google Scholar 

  18. Ulrich EL, Akutsu H, Doreleijers JF, Harano Y, Ioannidis YE, Lin J et al (2008) BioMagResBank. Nucl Acids Res 36(suppl 1):402–408

    Google Scholar 

  19. Wishart DS, Jewison T, Guo AC, Wilson M, Knox C, Liu Y et al (2012) HMDB 3.0--the human metabolome database in 2013. Nucl Acids Res 41(Database issue):D801–D807

    Article  Google Scholar 

  20. Wishart DS, Knox C, Guo AC, Eisner R, Young N, Gautam B et al (2008) HMDB: a knowledgebase for the human metabolome. Nucleic Acids Res 37(Database issue):D603–D610

    PubMed  PubMed Central  Google Scholar 

  21. Wishart DS, Tzur D, Knox C, Eisner R, Guo AC, Young N et al (2007) HMDB: the human Metabolome database. Nucleic Acids Res 35(Database issue):D521–D526

    Article  CAS  Google Scholar 

  22. Dashti H, Westler WM, Tonelli M, Wedell JR, Markley JL, Eghbalnia HR (2007) Spin system modeling of nuclear magnetic resonance spectra for applications in metabolomics and small molecule screening. Anal Chem 89(22):12201–12208

    Article  Google Scholar 

  23. Dashti H, Westler WM, Markley JL, Eghbalnia HR (2017) Unique identifiers for small molecules enable rigorous labeling of their atoms. Sci Data 4:170073

    Article  Google Scholar 

  24. Pupier M, Nuzillard JM, Wist J, Schlörer Nils E, Kuhn S, Erdelyi M et al (2018) NMReDATA, a standard to report the NMR assignment and parameters of organic compounds. Magn Reson Chem 56(8):703–715

    Article  CAS  Google Scholar 

  25. Anderson WA, McConnell HM (1957) Analysis of high-resolution NMR spectra. J Chem Phys 26:1496

    Article  CAS  Google Scholar 

  26. Corio PL (1960) The analysis of nuclear magnetic resonance spectra. Chem Rev 60:363–429

    Article  CAS  Google Scholar 

  27. Binev Y, Marques MMB, Aires-de-Sousa J (2007) Prediction of 1H NMR coupling constants with associative neural networks trained for chemical shifts. J Chem Inform Modeling 47(6):2089–2097

    Article  CAS  Google Scholar 

  28. Smith SA, Levante TO, Meier BH, Ernst RR (1994) Computer simulations in magnetic resonance. An object-oriented programming approach. J Magn Reson Series A 106(1):75–105

    Article  CAS  Google Scholar 

  29. Goodwin DL, Kuprov I (2015) Auxiliary matrix formalism for interaction representation transformations, optimal control, and spin relaxation theories. J Chem Phys 143(8):084113

    Article  CAS  Google Scholar 

  30. Cheshkov DA, Sinitsyn DO, Sheberstov KF, Chertkov VA (2016) Total lineshape analysis of high-resolution NMR spectra powered by simulated annealing. J Magn Reson 272:10–19

    Article  CAS  Google Scholar 

  31. Laatikainen R, Niemitz M, Weber U, Sundelin J, Hassinen T, Vepsäläinen J (1996) General strategies for total-Lineshape-type spectral analysis of NMR spectra using integral-transform iterator. J Mag Reson Series A 120(1):1–10

    Article  CAS  Google Scholar 

  32. Stephenson DS, Binsch G (1980) Automated analysis of high-resolution NMR spectra. I. Principles and computational strategy. JMagReson (1969) 37(3):395–407

    Article  CAS  Google Scholar 

  33. Dashti H, Wedell JR, Westler WM, Tonelli M, Aceti D, Amarasinghe GK et al (2018) Applications of parametrized NMR spin systems of small molecules. Anal Chem 90(18):10646–10649

    Article  CAS  Google Scholar 

  34. Dashti H, Wedell JR, Cornilescu G, Schwieters C, Westler WM, Markley JL et al (2018) Robust nomenclature and software for enhanced reproducibility in molecular modeling of small molecules. bioRxiv:429530. https://doi.org/10.1101/429530

  35. Norris M, Fetler B, Marchant J, Johnson BA (2016) NMRFx processor: a cross-platform NMR data processing program. J Biomol NMR 65(3–4):205–216

    Article  CAS  Google Scholar 

  36. Maciejewski MW, Schuyler AD, Gryk MR, Moraru I, Romero PR, Ulrich ER et al (2017) NMRbox: a resource for biomolecular NMR computation. Biophy J 112(8):1529–1534

    Article  CAS  Google Scholar 

  37. Ulrich EL, Baskaran K, Dashti H, Ioannidis YE, Livny M, Romero PR et al (2018) NMR-STAR: comprehensive ontology for representing, archiving and exchanging data from nuclear magnetic resonance spectroscopic experiments. J Biomol NMR. https://doi.org/10.1007/s10858-018-0220-3. [Epub ahead of print]

    Article  Google Scholar 

  38. Salek RM, Neumann S, Schober D, Hummel J, Billiau K, Kopka J et al (2015) Coordination of standards in metabolomics (COSMOS): facilitating integrated metabolomics data access. Metabolomics 11(6):1587–1597

    Article  CAS  Google Scholar 

  39. Hall SR (1991) The STAR file: a new format for electronic data transfer and archiving. J Chem Inf Comput Sci 31:326–333

    Article  CAS  Google Scholar 

  40. Hall SR, Cook APF (1995) STAR dictionary definition language: initial specification. J Chem Inf Comput Sci 35:819–825

    Article  CAS  Google Scholar 

  41. Fitzgerald PMD, Westbrook JD, Bourne PE, McMahon B, Watenpaugh KD, Berman HM (2005) 4.5 macromolecular dictionary (mmCIF). In: International tables for crystallography G definition and exchange of crystallographic dataedited by Hall SR, McMahon B. Springer, Dordrecht, pp 295–443

    Google Scholar 

  42. Ulrich EL, Argentar D, Klimowicz A, Markley JL (1996) STAR/CIF macromolecular NMR data dictionaries and data file formats. Acta Crystallogr A 52(a1):C577–C577

    Article  Google Scholar 

Download references

Acknowledgments

This work received funding from the National Institutes of Health (NIH). Grants from the NIH National Institute of General Medical Science provided support to the National Magnetic Resonance Facility at Madison (P41 GM103399) and the Biological Magnetic Resonance Data Bank (R01 GM109046) and partial support for HRE, HD, and JRW (P41 GM111135 to the National Center for Biomolecular NMR Data Processing and Analysis). H.D. currently is supported by National Heart, Lung, and Blood Institute grant T32 HL007575.

Author information

Author notes

  1. Hesam Dashti

    Present address: Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

Authors and Affiliations

  1. Department of Biochemistry, University of Wisconsin Madison, Madison, WI, USA

    John L. Markley, Jonathan R. Wedell, William M. Westler & Hamid R. Eghbalnia

Authors
  1. John L. Markley
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hesam Dashti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jonathan R. Wedell
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. William M. Westler
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hamid R. Eghbalnia
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John L. Markley .

Editor information

Editors and Affiliations

  1. Northwest Metabolomics Research Center, Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA, USA

    G. A. Nagana Gowda

  2. Northwest Metabolomics Research Center, Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, Fred Hutch Cancer Research Center, Seattle, WA, USA

    Daniel Raftery

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Science+Business Media, LLC, part of Springer Nature

About this protocol

Check for updates. Verify currency and authenticity via CrossMark

Cite this protocol

Markley, J.L., Dashti, H., Wedell, J.R., Westler, W.M., Eghbalnia, H.R. (2019). Tools for Enhanced NMR-Based Metabolomics Analysis. In: Gowda, G., Raftery, D. (eds) NMR-Based Metabolomics. Methods in Molecular Biology, vol 2037. Humana, New York, NY. https://doi.org/10.1007/978-1-4939-9690-2_23

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-9690-2_23

  • Published:

  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-4939-9689-6

  • Online ISBN: 978-1-4939-9690-2

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation