Structure Elucidation of Unknown Metabolites in Metabolomics by Combined NMR and MS/MS Prediction
Abstract
Here, we introduce a cheminformatics approach that combines highly selective and orthogonal structure elucidation parameters; accurate mass, MS/MS (MS2), and NMR in a single analysis platform to accurately identify unknown metabolites in untargeted studies. The approach starts with an unknown LC-MS feature, and then combines the experimental MS/MS and NMR information of the unknown to effectively filter the false positive candidate structures based on their predicted MS/MS and NMR spectra. We demonstrate the approach on a model mixture and then we identify an uncatalogued secondary metabolite in Arabidopsis thaliana. The NMR/MS2 approach is well suited for discovery of new metabolites in plant extracts, microbes, soils, dissolved organic matter, food extracts, biofuels, and biomedical samples, facilitating the identification of metabolites that are not present in experimental NMR and MS metabolomics databases.
- Authors:
-
[1]
- Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
- Univ. of Kansas, Lawrence, KS (United States)
- Publication Date:
- Research Org.:
- Pacific Northwest National Laboratory (PNNL), Richland, WA (United States). Environmental Molecular Sciences Laboratory (EMSL)
- Sponsoring Org.:
- USDOE
- OSTI Identifier:
- 1421319
- Report Number(s):
- PNNL-SA-129343
Journal ID: ISSN 2218-1989; METALU; 49679
- Grant/Contract Number:
- AC05-76RL01830
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Metabolites
- Additional Journal Information:
- Journal Volume: 8; Journal Issue: 1; Journal ID: ISSN 2218-1989
- Publisher:
- MDPI
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 54 ENVIRONMENTAL SCIENCES; Environmental Molecular Sciences Laboratory; metabolomics; metabolite identification; hybrid MS/NMR method; in silico fragmentation; chemical shift prediction; Arabidopsis thaliana metabolome
Citation Formats
Boiteau, Rene M., Hoyt, David W., Nicora, Carrie D., Kinmonth-Schultz, Hannah A., Ward, Joy K., and Bingol, Kerem. Structure Elucidation of Unknown Metabolites in Metabolomics by Combined NMR and MS/MS Prediction. United States: N. p., 2018.
Web. doi:10.3390/metabo8010008.
Boiteau, Rene M., Hoyt, David W., Nicora, Carrie D., Kinmonth-Schultz, Hannah A., Ward, Joy K., & Bingol, Kerem. Structure Elucidation of Unknown Metabolites in Metabolomics by Combined NMR and MS/MS Prediction. United States. https://doi.org/10.3390/metabo8010008
Boiteau, Rene M., Hoyt, David W., Nicora, Carrie D., Kinmonth-Schultz, Hannah A., Ward, Joy K., and Bingol, Kerem. Wed .
"Structure Elucidation of Unknown Metabolites in Metabolomics by Combined NMR and MS/MS Prediction". United States. https://doi.org/10.3390/metabo8010008. https://www.osti.gov/servlets/purl/1421319.
@article{osti_1421319,
title = {Structure Elucidation of Unknown Metabolites in Metabolomics by Combined NMR and MS/MS Prediction},
author = {Boiteau, Rene M. and Hoyt, David W. and Nicora, Carrie D. and Kinmonth-Schultz, Hannah A. and Ward, Joy K. and Bingol, Kerem},
abstractNote = {Here, we introduce a cheminformatics approach that combines highly selective and orthogonal structure elucidation parameters; accurate mass, MS/MS (MS2), and NMR in a single analysis platform to accurately identify unknown metabolites in untargeted studies. The approach starts with an unknown LC-MS feature, and then combines the experimental MS/MS and NMR information of the unknown to effectively filter the false positive candidate structures based on their predicted MS/MS and NMR spectra. We demonstrate the approach on a model mixture and then we identify an uncatalogued secondary metabolite in Arabidopsis thaliana. The NMR/MS2 approach is well suited for discovery of new metabolites in plant extracts, microbes, soils, dissolved organic matter, food extracts, biofuels, and biomedical samples, facilitating the identification of metabolites that are not present in experimental NMR and MS metabolomics databases.},
doi = {10.3390/metabo8010008},
journal = {Metabolites},
number = 1,
volume = 8,
place = {United States},
year = {Wed Jan 17 00:00:00 EST 2018},
month = {Wed Jan 17 00:00:00 EST 2018}
}
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Works referenced in this record:
Accurate Identification of Unknown and Known Metabolic Mixture Components by Combining 3D NMR with Fourier Transform Ion Cyclotron Resonance Tandem Mass Spectrometry
journal, September 2017
- Wang, Cheng; He, Lidong; Li, Da-Wei
- Journal of Proteome Research, Vol. 16, Issue 10
The evolving role of natural products in drug discovery
journal, February 2005
- Koehn, Frank E.; Carter, Guy T.
- Nature Reviews Drug Discovery, Vol. 4, Issue 3
Metabolic phenotyping in clinical and surgical environments
journal, November 2012
- Nicholson, Jeremy K.; Holmes, Elaine; Kinross, James M.
- Nature, Vol. 491, Issue 7424
Metabolite Measurement: Pitfalls to Avoid and Practices to Follow
journal, June 2017
- Lu, Wenyun; Su, Xiaoyang; Klein, Matthias S.
- Annual Review of Biochemistry, Vol. 86, Issue 1
Carbon Backbone Topology of the Metabolome of a Cell
journal, May 2012
- Bingol, Kerem; Zhang, Fengli; Bruschweiler-Li, Lei
- Journal of the American Chemical Society, Vol. 134, Issue 21
Proton and carbon-13 assignments from sensitivity-enhanced detection of heteronuclear multiple-bond connectivity by 2D multiple quantum NMR
journal, April 1986
- Bax, Ad.; Summers, Michael F.
- Journal of the American Chemical Society, Vol. 108, Issue 8
Competitive fragmentation modeling of ESI-MS/MS spectra for putative metabolite identification
journal, June 2014
- Allen, Felicity; Greiner, Russ; Wishart, David
- Metabolomics, Vol. 11, Issue 1
Coherence transfer by isotropic mixing: Application to proton correlation spectroscopy
journal, July 1983
- Braunschweiler, L.; Ernst, R. R.
- Journal of Magnetic Resonance (1969), Vol. 53, Issue 3
Sensitivity-enhanced two-dimensional heteronuclear relayed coherence transfer NMR spectroscopy
journal, September 1986
- Lerner, Laura; Bax, Ad
- Journal of Magnetic Resonance (1969), Vol. 69, Issue 2
Natural abundance nitrogen-15 NMR by enhanced heteronuclear spectroscopy
journal, January 1980
- Bodenhausen, Geoffrey; Ruben, David J.
- Chemical Physics Letters, Vol. 69, Issue 1
KEGG: Kyoto Encyclopedia of Genes and Genomes
journal, January 2000
- Kanehisa, Minoru; Goto, Susumu
- Nucleic Acids Research, Vol. 28, Issue 1, p. 27-30
Knowns and unknowns in metabolomics identified by multidimensional NMR and hybrid MS/NMR methods
journal, February 2017
- Bingol, Kerem; Brüschweiler, Rafael
- Current Opinion in Biotechnology, Vol. 43
Liquid chromatography quadrupole time-of-flight mass spectrometry characterization of metabolites guided by the METLIN database
journal, February 2013
- Zhu, Zheng-Jiang; Schultz, Andrew W.; Wang, Junhua
- Nature Protocols, Vol. 8, Issue 3
Metabolomics-assisted synthetic biology
journal, February 2012
- Ellis, David I.; Goodacre, Royston
- Current Opinion in Biotechnology, Vol. 23, Issue 1
The future of NMR-based metabolomics
journal, February 2017
- Markley, John L.; Brüschweiler, Rafael; Edison, Arthur S.
- Current Opinion in Biotechnology, Vol. 43
The Impact of the Absence of Aliphatic Glucosinolates on Insect Herbivory in Arabidopsis
journal, April 2008
- Beekwilder, Jules; van Leeuwen, Wessel; van Dam, Nicole M.
- PLoS ONE, Vol. 3, Issue 4
BioMagResBank
journal, December 2007
- Ulrich, E. L.; Akutsu, H.; Doreleijers, J. F.
- Nucleic Acids Research, Vol. 36, Issue Database
Metabolomics Beyond Spectroscopic Databases: A Combined MS/NMR Strategy for the Rapid Identification of New Metabolites in Complex Mixtures
journal, March 2015
- Bingol, Kerem; Bruschweiler-Li, Lei; Yu, Cao
- Analytical Chemistry, Vol. 87, Issue 7
Cruciferous vegetables and human cancer risk: epidemiologic evidence and mechanistic basis
journal, March 2007
- Higdon, J.; Delage, B.; Williams, D.
- Pharmacological Research, Vol. 55, Issue 3
MIDAS: A Database-Searching Algorithm for Metabolite Identification in Metabolomics
journal, September 2014
- Wang, Yingfeng; Kora, Guruprasad; Bowen, Benjamin P.
- Analytical Chemistry, Vol. 86, Issue 19
13 C NMR Metabolomics: INADEQUATE Network Analysis
journal, May 2015
- Clendinen, Chaevien S.; Pasquel, Christian; Ajredini, Ramadan
- Analytical Chemistry, Vol. 87, Issue 11
Unified and Isomer-Specific NMR Metabolomics Database for the Accurate Analysis of 13 C– 1 H HSQC Spectra
journal, November 2014
- Bingol, Kerem; Li, Da-Wei; Bruschweiler-Li, Lei
- ACS Chemical Biology, Vol. 10, Issue 2
Genetic Control of Natural Variation in Arabidopsis Glucosinolate Accumulation
journal, June 2001
- Kliebenstein, Daniel J.; Kroymann, Juergen; Brown, Paul
- Plant Physiology, Vol. 126, Issue 2
MZmine 2: Modular framework for processing, visualizing, and analyzing mass spectrometry-based molecular profile data
journal, July 2010
- Pluskal, Tomáš; Castillo, Sandra; Villar-Briones, Alejandro
- BMC Bioinformatics, Vol. 11, Issue 1
Recent applications of metabolomics to advance microbial biofuel production
journal, February 2017
- Martien, Julia I.; Amador-Noguez, Daniel
- Current Opinion in Biotechnology, Vol. 43
ChemSpider: An Online Chemical Information Resource
journal, November 2010
- Pence, Harry E.; Williams, Antony
- Journal of Chemical Education, Vol. 87, Issue 11
MetFrag relaunched: incorporating strategies beyond in silico fragmentation
journal, January 2016
- Ruttkies, Christoph; Schymanski, Emma L.; Wolf, Sebastian
- Journal of Cheminformatics, Vol. 8, Issue 1
Comprehensive Metabolite Identification Strategy Using Multiple Two-Dimensional NMR Spectra of a Complex Mixture Implemented in the COLMARm Web Server
journal, December 2016
- Bingol, Kerem; Li, Da-Wei; Zhang, Bo
- Analytical Chemistry, Vol. 88, Issue 24
Unambiguous metabolite identification in high-throughput metabolomics by hybrid 1D 1 H NMR/ESI MS 1 approach : Hybrid 1D
journal, September 2016
- Walker, Lawrence R.; Hoyt, David W.; Walker, S. Michael
- Magnetic Resonance in Chemistry, Vol. 54, Issue 12
The Effect of Molecular Conformation on the Accuracy of Theoretical 1 H and 13 C Chemical Shifts Calculated by Ab Initio Methods for Metabolic Mixture Analysis
journal, March 2016
- Chikayama, Eisuke; Shimbo, Yudai; Komatsu, Keiko
- The Journal of Physical Chemistry B, Vol. 120, Issue 14
Structure and Metabolic-Flow Analysis of Molecular Complexity in a 13 C-Labeled Tree by 2D and 3D NMR
journal, April 2016
- Komatsu, Takanori; Ohishi, Risa; Shino, Amiu
- Angewandte Chemie, Vol. 128, Issue 20
Improved Quantum Chemical NMR Chemical Shift Prediction of Metabolites in Aqueous Solution toward the Validation of Unknowns
journal, April 2017
- Hoffmann, Felix; Li, Da-Wei; Sebastiani, Daniel
- The Journal of Physical Chemistry A, Vol. 121, Issue 16
Environmental metabolomics: a critical review and future perspectives
journal, December 2008
- Bundy, Jacob G.; Davey, Matthew P.; Viant, Mark R.
- Metabolomics, Vol. 5, Issue 1
Searching molecular structure databases with tandem mass spectra using CSI:FingerID
journal, September 2015
- Dührkop, Kai; Shen, Huibin; Meusel, Marvin
- Proceedings of the National Academy of Sciences, Vol. 112, Issue 41
HMDB 3.0—The Human Metabolome Database in 2013
journal, November 2012
- Wishart, David S.; Jewison, Timothy; Guo, An Chi
- Nucleic Acids Research, Vol. 41, Issue D1
Integrating ion mobility spectrometry into mass spectrometry-based exposome measurements: what can it add and how far can it go?
journal, January 2017
- Metz, Thomas O.; Baker, Erin S.; Schymanski, Emma L.
- Bioanalysis, Vol. 9, Issue 1
The food metabolome: a window over dietary exposure
journal, April 2014
- Scalbert, Augustin; Brennan, Lorraine; Manach, Claudine
- The American Journal of Clinical Nutrition, Vol. 99, Issue 6
MOLGEN+, a generator of connectivity isomers and stereoisomers for molecular structure elucidation
journal, October 1995
- Benecke, C.; Grund, R.; Hohberger, R.
- Analytica Chimica Acta, Vol. 314, Issue 3
Multi-functionality of a tryptophan residue conserved in substrate-binding groove of GH19 chitinases
journal, January 2021
- Nagata, Takuya; Shinya, Shoko; Ohnuma, Takayuki
- Scientific Reports, Vol. 11, Issue 1
A multi-omic characterization of temperature stress in a halotolerant Scenedesmus strain for algal biotechnology
journal, March 2021
- Calhoun, Sara; Bell, Tisza Ann Szeremy; Dahlin, Lukas R.
- Communications Biology, Vol. 4, Issue 1
MetFrag relaunched: incorporating strategies beyond in silico fragmentation
text, January 2016
- Ruttkies, Christoph; Schymanski, Emma L.; Wolf, Sebastian
- ETH Zurich
Structure and Metabolic‐Flow Analysis of Molecular Complexity in a 13 C‐Labeled Tree by 2D and 3D NMR
journal, April 2016
- Komatsu, Takanori; Ohishi, Risa; Shino, Amiu
- Angewandte Chemie International Edition, Vol. 55, Issue 20
Competitive Fragmentation Modeling of ESI-MS/MS spectra for putative metabolite identification
text, January 2013
- Allen, F.; Greiner, R.; Wishart, D.
- arXiv
Structure and Metabolic-Flow Analysis of Molecular Complexity in a 13 C-Labeled Tree by 2D and 3D NMR
journal, April 2016
- Komatsu, Takanori; Ohishi, Risa; Shino, Amiu
- Angewandte Chemie, Vol. 128, Issue 20
Environmental metabolomics: a critical review and future perspectives
journal, December 2008
- Bundy, Jacob G.; Davey, Matthew P.; Viant, Mark R.
- Metabolomics, Vol. 5, Issue 1
Competitive fragmentation modeling of ESI-MS/MS spectra for putative metabolite identification
journal, June 2014
- Allen, Felicity; Greiner, Russ; Wishart, David
- Metabolomics, Vol. 11, Issue 1
Coherence transfer by isotropic mixing: Application to proton correlation spectroscopy
journal, July 1983
- Braunschweiler, L.; Ernst, R. R.
- Journal of Magnetic Resonance (1969), Vol. 53, Issue 3
Sensitivity-enhanced two-dimensional heteronuclear relayed coherence transfer NMR spectroscopy
journal, September 1986
- Lerner, Laura; Bax, Ad
- Journal of Magnetic Resonance (1969), Vol. 69, Issue 2
Knowns and unknowns in metabolomics identified by multidimensional NMR and hybrid MS/NMR methods
journal, February 2017
- Bingol, Kerem; Brüschweiler, Rafael
- Current Opinion in Biotechnology, Vol. 43
The future of NMR-based metabolomics
journal, February 2017
- Markley, John L.; Brüschweiler, Rafael; Edison, Arthur S.
- Current Opinion in Biotechnology, Vol. 43
Recent applications of metabolomics to advance microbial biofuel production
journal, February 2017
- Martien, Julia I.; Amador-Noguez, Daniel
- Current Opinion in Biotechnology, Vol. 43
MIDAS: A Database-Searching Algorithm for Metabolite Identification in Metabolomics
journal, September 2014
- Wang, Yingfeng; Kora, Guruprasad; Bowen, Benjamin P.
- Analytical Chemistry, Vol. 86, Issue 19
Metabolomics Beyond Spectroscopic Databases: A Combined MS/NMR Strategy for the Rapid Identification of New Metabolites in Complex Mixtures
journal, March 2015
- Bingol, Kerem; Bruschweiler-Li, Lei; Yu, Cao
- Analytical Chemistry, Vol. 87, Issue 7
13 C NMR Metabolomics: INADEQUATE Network Analysis
journal, May 2015
- Clendinen, Chaevien S.; Pasquel, Christian; Ajredini, Ramadan
- Analytical Chemistry, Vol. 87, Issue 11
Improved Quantum Chemical NMR Chemical Shift Prediction of Metabolites in Aqueous Solution toward the Validation of Unknowns
journal, April 2017
- Hoffmann, Felix; Li, Da-Wei; Sebastiani, Daniel
- The Journal of Physical Chemistry A, Vol. 121, Issue 16
The Effect of Molecular Conformation on the Accuracy of Theoretical 1 H and 13 C Chemical Shifts Calculated by Ab Initio Methods for Metabolic Mixture Analysis
journal, March 2016
- Chikayama, Eisuke; Shimbo, Yudai; Komatsu, Keiko
- The Journal of Physical Chemistry B, Vol. 120, Issue 14
Accurate Identification of Unknown and Known Metabolic Mixture Components by Combining 3D NMR with Fourier Transform Ion Cyclotron Resonance Tandem Mass Spectrometry
journal, September 2017
- Wang, Cheng; He, Lidong; Li, Da-Wei
- Journal of Proteome Research, Vol. 16, Issue 10
ChemSpider: An Online Chemical Information Resource
journal, November 2010
- Pence, Harry E.; Williams, Antony
- Journal of Chemical Education, Vol. 87, Issue 11
Proton and carbon-13 assignments from sensitivity-enhanced detection of heteronuclear multiple-bond connectivity by 2D multiple quantum NMR
journal, April 1986
- Bax, Ad.; Summers, Michael F.
- Journal of the American Chemical Society, Vol. 108, Issue 8
Carbon Backbone Topology of the Metabolome of a Cell
journal, May 2012
- Bingol, Kerem; Zhang, Fengli; Bruschweiler-Li, Lei
- Journal of the American Chemical Society, Vol. 134, Issue 21
Metabolic phenotyping in clinical and surgical environments
journal, November 2012
- Nicholson, Jeremy K.; Holmes, Elaine; Kinross, James M.
- Nature, Vol. 491, Issue 7424
The evolving role of natural products in drug discovery
journal, February 2005
- Koehn, Frank E.; Carter, Guy T.
- Nature Reviews Drug Discovery, Vol. 4, Issue 3
Red versus green leaves: transcriptomic comparison of foliar senescence between two Prunus cerasifera genotypes
journal, February 2020
- Vangelisti, Alberto; Guidi, Lucia; Cavallini, Andrea
- Scientific Reports, Vol. 10, Issue 1
BioMagResBank
journal, December 2007
- Ulrich, E. L.; Akutsu, H.; Doreleijers, J. F.
- Nucleic Acids Research, Vol. 36, Issue Database
HMDB 3.0—The Human Metabolome Database in 2013
journal, November 2012
- Wishart, David S.; Jewison, Timothy; Guo, An Chi
- Nucleic Acids Research, Vol. 41, Issue D1
MetFrag relaunched: incorporating strategies beyond in silico fragmentation
journal, January 2016
- Ruttkies, Christoph; Schymanski, Emma L.; Wolf, Sebastian
- Journal of Cheminformatics, Vol. 8, Issue 1
A multi-omics approach unravels metagenomic and metabolic alterations of a probiotic and synbiotic additive in rainbow trout (Oncorhynchus mykiss)
journal, January 2022
- Rasmussen, Jacob Agerbo; Villumsen, Kasper Rømer; Ernst, Madeleine
- Microbiome, Vol. 10, Issue 1
The Impact of the Absence of Aliphatic Glucosinolates on Insect Herbivory in Arabidopsis
journal, April 2008
- Beekwilder, Jules; van Leeuwen, Wessel; van Dam, Nicole M.
- PLoS ONE, Vol. 3, Issue 4
The food metabolome: a window over dietary exposure
journal, April 2014
- Scalbert, Augustin; Brennan, Lorraine; Manach, Claudine
- The American Journal of Clinical Nutrition, Vol. 99, Issue 6
Integrating ion mobility spectrometry into mass spectrometry-based exposome measurements: what can it add and how far can it go?
journal, January 2017
- Metz, Thomas O.; Baker, Erin S.; Schymanski, Emma L.
- Bioanalysis, Vol. 9, Issue 1
Works referencing / citing this record:
Hochdurchsatz‐Metabolomik mit 1D‐NMR
journal, November 2018
- Vignoli, Alessia; Ghini, Veronica; Meoni, Gaia
- Angewandte Chemie, Vol. 131, Issue 4
Statistically correlating NMR spectra and LC-MS data to facilitate the identification of individual metabolites in metabolomics mixtures
journal, February 2019
- Li, Xing; Luo, Huan; Huang, Tao
- Analytical and Bioanalytical Chemistry, Vol. 411, Issue 7
Cancer metabolomic markers in urine: evidence, techniques and recommendations
journal, May 2019
- Dinges, Sarah S.; Hohm, Annika; Vandergrift, Lindsey A.
- Nature Reviews Urology, Vol. 16, Issue 6
Phytochemical Profile and Antimicrobial Effects of Different Medicinal Plant: Current Knowledge and Future Perspectives
journal, January 2020
- Mulat, Mulugeta; Khan, Fazlurrahman; Muluneh, Gizachew
- Current Traditional Medicine, Vol. 6, Issue 1
Recent Advances in Targeted and Untargeted Metabolomics by NMR and MS/NMR Methods
journal, April 2018
- Bingol, Kerem
- High-Throughput, Vol. 7, Issue 2
Metabolomics: A Way Forward for Crop Improvement
journal, December 2019
- Razzaq, Ali; Sadia, Bushra; Raza, Ali
- Metabolites, Vol. 9, Issue 12
A Deeper Investigation of Drug Degradation Mixtures Using a Combination of MS and NMR Data: Application to Indapamide
journal, May 2019
- Palaric, Cécile; Molinié, Roland; Cailleu, Dominique
- Molecules, Vol. 24, Issue 9
Large Scale Proteomic Data and Network-Based Systems Biology Approaches to Explore the Plant World
journal, June 2018
- Di Silvestre, Dario; Bergamaschi, Andrea; Bellini, Edoardo
- Proteomes, Vol. 6, Issue 2
High‐Throughput Metabolomics by 1D NMR
journal, January 2019
- Vignoli, Alessia; Ghini, Veronica; Meoni, Gaia
- Angewandte Chemie International Edition, Vol. 58, Issue 4
Metabolomics: A Way Forward for Crop Improvement
journal, December 2019
- Razzaq, Ali; Sadia, Bushra; Raza, Ali
- Metabolites, Vol. 9, Issue 12
Rice Secondary Metabolites: Structures, Roles, Biosynthesis, and Metabolic Regulation
journal, November 2018
- Wang, Weixuan; Li, Yuying; Dang, Pengqin
- Molecules, Vol. 23, Issue 12
A Deeper Investigation of Drug Degradation Mixtures Using a Combination of MS and NMR Data: Application to Indapamide
journal, May 2019
- Palaric, Cécile; Molinié, Roland; Cailleu, Dominique
- Molecules, Vol. 24, Issue 9
Large Scale Proteomic Data and Network-Based Systems Biology Approaches to Explore the Plant World
journal, June 2018
- Di Silvestre, Dario; Bergamaschi, Andrea; Bellini, Edoardo
- Proteomes, Vol. 6, Issue 2