Peak Annotation and Verification Engine for Untargeted LC–MS Metabolomics
Abstract
Untargeted metabolomics can detect more than 10 000 peaks in a single LC–MS run. The correspondence between these peaks and metabolites, however, remains unclear. Here in this study, we introduce a Peak Annotation and Verification Engine (PAVE) for annotating untargeted microbial metabolomics data. The workflow involves growing cells in 13C and 15N isotope-labeled media to identify peaks from biological compounds and their carbon and nitrogen atom counts. Improved deisotoping and deadducting are enabled by algorithms that integrate positive mode, negative mode, and labeling data. To distinguish metabolites and their fragments, PAVE experimentally measures the response of each peak to weak in-source collision induced dissociation, which increases the peak intensity for fragments while decreasing it for their parent ions. The molecular formulas of the putative metabolites are then assigned based on database searching using both m/z and C/N atom counts. Application of this procedure to Saccharomyces cerevisiae and Escherichia coli revealed that more than 80% of peaks do not label, i.e., are environmental contaminants. More than 70% of the biological peaks are isotopic variants, adducts, fragments, or mass spectrometry artifacts yielding ~2000 apparent metabolites across the two organisms. About 650 match to a known metabolite formula based on m/z and C/Nmore »
- Authors:
-
[2];
[1];
[1]
- Princeton Univ., NJ (United States)
- Princeton Univ., NJ (United States); Rutgers Univ., New Brunswick, NJ (United States)
- Publication Date:
- Research Org.:
- Center for Advanced Bioenergy and Bioproducts Innovation (CABBI), Urbana, IL (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Biological and Environmental Research (BER)
- OSTI Identifier:
- 1491815
- Grant/Contract Number:
- SC0018420; SC0018260; FG02-02ER15344
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Analytical Chemistry
- Additional Journal Information:
- Journal Volume: 91; Journal Issue: 3; Journal ID: ISSN 0003-2700
- Publisher:
- American Chemical Society (ACS)
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
Citation Formats
Wang, Lin, Xing, Xi, Chen, Li, Yang, Lifeng, Su, Xiaoyang, Rabitz, Herschel, Lu, Wenyun, and Rabinowitz, Joshua D. Peak Annotation and Verification Engine for Untargeted LC–MS Metabolomics. United States: N. p., 2018.
Web. doi:10.1021/acs.analchem.8b03132.
Wang, Lin, Xing, Xi, Chen, Li, Yang, Lifeng, Su, Xiaoyang, Rabitz, Herschel, Lu, Wenyun, & Rabinowitz, Joshua D. Peak Annotation and Verification Engine for Untargeted LC–MS Metabolomics. United States. https://doi.org/10.1021/acs.analchem.8b03132
Wang, Lin, Xing, Xi, Chen, Li, Yang, Lifeng, Su, Xiaoyang, Rabitz, Herschel, Lu, Wenyun, and Rabinowitz, Joshua D. Wed .
"Peak Annotation and Verification Engine for Untargeted LC–MS Metabolomics". United States. https://doi.org/10.1021/acs.analchem.8b03132. https://www.osti.gov/servlets/purl/1491815.
@article{osti_1491815,
title = {Peak Annotation and Verification Engine for Untargeted LC–MS Metabolomics},
author = {Wang, Lin and Xing, Xi and Chen, Li and Yang, Lifeng and Su, Xiaoyang and Rabitz, Herschel and Lu, Wenyun and Rabinowitz, Joshua D.},
abstractNote = {Untargeted metabolomics can detect more than 10 000 peaks in a single LC–MS run. The correspondence between these peaks and metabolites, however, remains unclear. Here in this study, we introduce a Peak Annotation and Verification Engine (PAVE) for annotating untargeted microbial metabolomics data. The workflow involves growing cells in 13C and 15N isotope-labeled media to identify peaks from biological compounds and their carbon and nitrogen atom counts. Improved deisotoping and deadducting are enabled by algorithms that integrate positive mode, negative mode, and labeling data. To distinguish metabolites and their fragments, PAVE experimentally measures the response of each peak to weak in-source collision induced dissociation, which increases the peak intensity for fragments while decreasing it for their parent ions. The molecular formulas of the putative metabolites are then assigned based on database searching using both m/z and C/N atom counts. Application of this procedure to Saccharomyces cerevisiae and Escherichia coli revealed that more than 80% of peaks do not label, i.e., are environmental contaminants. More than 70% of the biological peaks are isotopic variants, adducts, fragments, or mass spectrometry artifacts yielding ~2000 apparent metabolites across the two organisms. About 650 match to a known metabolite formula based on m/z and C/N atom counts, with 220 assigned structures based on MS/MS and/or retention time to match to authenticated standards. Lastly, PAVE enables systematic annotation of LC–MS metabolomics data with only ~4% of peaks annotated as apparent metabolites.},
doi = {10.1021/acs.analchem.8b03132},
journal = {Analytical Chemistry},
number = 3,
volume = 91,
place = {United States},
year = {2018},
month = {12}
}
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Works referenced in this record:
Emerging applications of metabolomics in drug discovery and precision medicine
journal, March 2016
- Wishart, David S.
- Nature Reviews Drug Discovery, Vol. 15, Issue 7
Interactive XCMS Online: Simplifying Advanced Metabolomic Data Processing and Subsequent Statistical Analyses
journal, June 2014
- Gowda, Harsha; Ivanisevic, Julijana; Johnson, Caroline H.
- Analytical Chemistry, Vol. 86, Issue 14
Systems biology guided by XCMS Online metabolomics
journal, April 2017
- Huan, Tao; Forsberg, Erica M.; Rinehart, Duane
- Nature Methods, Vol. 14, Issue 5
XCMS: Processing Mass Spectrometry Data for Metabolite Profiling Using Nonlinear Peak Alignment, Matching, and Identification
journal, February 2006
- Smith, Colin A.; Want, Elizabeth J.; O'Maille, Grace
- Analytical Chemistry, Vol. 78, Issue 3
MZmine: toolbox for processing and visualization of mass spectrometry based molecular profile data
journal, January 2006
- Katajamaa, M.; Miettinen, J.; Oresic, M.
- Bioinformatics, Vol. 22, Issue 5
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
MetAlign: Interface-Driven, Versatile Metabolomics Tool for Hyphenated Full-Scan Mass Spectrometry Data Preprocessing
journal, March 2009
- Lommen, Arjen
- Analytical Chemistry, Vol. 81, Issue 8
MS-DIAL: data-independent MS/MS deconvolution for comprehensive metabolome analysis
journal, May 2015
- Tsugawa, Hiroshi; Cajka, Tomas; Kind, Tobias
- Nature Methods, Vol. 12, Issue 6
Annotation: A Computational Solution for Streamlining Metabolomics Analysis
journal, November 2017
- Domingo-Almenara, Xavier; Montenegro-Burke, J. Rafael; Benton, H. Paul
- Analytical Chemistry, Vol. 90, Issue 1
Bioinformatics: The Next Frontier of Metabolomics
journal, November 2014
- Johnson, Caroline H.; Ivanisevic, Julijana; Benton, H. Paul
- Analytical Chemistry, Vol. 87, Issue 1
Analytical Methods in Untargeted Metabolomics: State of the Art in 2015
journal, March 2015
- Alonso, Arnald; Marsal, Sara; Julià , Antonio
- Frontiers in Bioengineering and Biotechnology, Vol. 3
CAMERA: An Integrated Strategy for Compound Spectra Extraction and Annotation of Liquid Chromatography/Mass Spectrometry Data Sets
journal, December 2011
- Kuhl, Carsten; Tautenhahn, Ralf; Böttcher, Christoph
- Analytical Chemistry, Vol. 84, Issue 1
Mass Spectral Feature List Optimizer (MS-FLO): A Tool To Minimize False Positive Peak Reports in Untargeted Liquid Chromatography–Mass Spectroscopy (LC-MS) Data Processing
journal, March 2017
- DeFelice, Brian C.; Mehta, Sajjan Singh; Samra, Stephanie
- Analytical Chemistry, Vol. 89, Issue 6
Elemental formula annotation of polar and lipophilic metabolites using 13 C, 15 N and 34 S isotope labelling, in combination with high-resolution mass spectrometry
journal, July 2011
- Giavalisco, Patrick; Li, Yan; Matthes, Annemarie
- The Plant Journal, Vol. 68, Issue 2
Stable Isotope Assisted Assignment of Elemental Compositions for Metabolomics
journal, September 2007
- Hegeman, Adrian D.; Schulte, Christopher F.; Cui, Qiu
- Analytical Chemistry, Vol. 79, Issue 18
NTFD--a stand-alone application for the non-targeted detection of stable isotope-labeled compounds in GC/MS data
journal, March 2013
- Hiller, K.; Wegner, A.; Weindl, D.
- Bioinformatics, Vol. 29, Issue 9
Metabolomic Analysis and Visualization Engine for LC−MS Data
journal, December 2010
- Melamud, Eugene; Vastag, Livia; Rabinowitz, Joshua D.
- Analytical Chemistry, Vol. 82, Issue 23
PeakML/mzMatch: A File Format, Java Library, R Library, and Tool-Chain for Mass Spectrometry Data Analysis
journal, April 2011
- Scheltema, Richard A.; Jankevics, Andris; Jansen, Ritsert C.
- Analytical Chemistry, Vol. 83, Issue 7
mzMatch–ISO: an R tool for the annotation and relative quantification of isotope-labelled mass spectrometry data
journal, November 2012
- Chokkathukalam, Achuthanunni; Jankevics, Andris; Creek, Darren J.
- Bioinformatics, Vol. 29, Issue 2
X 13 CMS: Global Tracking of Isotopic Labels in Untargeted Metabolomics
journal, January 2014
- Huang, Xiaojing; Chen, Ying-Jr; Cho, Kevin
- Analytical Chemistry, Vol. 86, Issue 3
ALLocator: An Interactive Web Platform for the Analysis of Metabolomic LC-ESI-MS Datasets, Enabling Semi-Automated, User-Revised Compound Annotation and Mass Isotopomer Ratio Analysis
journal, November 2014
- Kessler, Nikolas; Walter, Frederik; Persicke, Marcus
- PLoS ONE, Vol. 9, Issue 11
Addressing the current bottlenecks of metabolomics: Isotopic Ratio Outlier Analysis™, an isotopic-labeling technique for accurate biochemical profiling
journal, September 2012
- de Jong, Felice A.; Beecher, Chris
- Bioanalysis, Vol. 4, Issue 18
Isotopic Ratio Outlier Analysis of the S. cerevisiae Metabolome Using Accurate Mass Gas Chromatography/Time-of-Flight Mass Spectrometry: A New Method for Discovery
journal, February 2016
- Qiu, Yunping; Moir, Robyn; Willis, Ian
- Analytical Chemistry, Vol. 88, Issue 5
Enhanced Isotopic Ratio Outlier Analysis (IROA) Peak Detection and Identification with Ultra-High Resolution GC-Orbitrap/MS: Potential Application for Investigation of Model Organism Metabolomes
journal, January 2018
- Qiu, Yunping; Moir, Robyn; Willis, Ian
- Metabolites, Vol. 8, Issue 1
MetExtract: a new software tool for the automated comprehensive extraction of metabolite-derived LC/MS signals in metabolomics research
journal, January 2012
- Bueschl, Christoph; Kluger, Bernhard; Berthiller, Franz
- Bioinformatics, Vol. 28, Issue 5
MetExtract II: A Software Suite for Stable Isotope-Assisted Untargeted Metabolomics
journal, August 2017
- Bueschl, Christoph; Kluger, Bernhard; Neumann, Nora K. N.
- Analytical Chemistry, Vol. 89, Issue 17
Systems-Level Annotation of a Metabolomics Data Set Reduces 25 000 Features to Fewer than 1000 Unique Metabolites
journal, September 2017
- Mahieu, Nathaniel G.; Patti, Gary J.
- Analytical Chemistry, Vol. 89, Issue 19
New methods to identify high peak density artifacts in Fourier transform mass spectra and to mitigate their effects on high-throughput metabolomic data analysis
journal, September 2018
- Mitchell, Joshua M.; Flight, Robert M.; Wang, Qing Jun
- Metabolomics, Vol. 14, Issue 10
Extraction and Quantitation of Nicotinamide Adenine Dinucleotide Redox Cofactors
journal, January 2018
- Lu, Wenyun; Wang, Lin; Chen, Li
- Antioxidants & Redox Signaling, Vol. 28, Issue 3
Employing ProteoWizard to Convert Raw Mass Spectrometry Data
journal, June 2014
- Holman, Jerry D.; Tabb, David L.; Mallick, Parag
- Current Protocols in Bioinformatics, Vol. 46, Issue 1
Detailed Investigation and Comparison of the XCMS and MZmine 2 Chromatogram Construction and Chromatographic Peak Detection Methods for Preprocessing Mass Spectrometry Metabolomics Data
journal, August 2017
- Myers, Owen D.; Sumner, Susan J.; Li, Shuzhao
- Analytical Chemistry, Vol. 89, Issue 17
Interferences and contaminants encountered in modern mass spectrometry
journal, October 2008
- Keller, Bernd O.; Sui, Jie; Young, Alex B.
- Analytica Chimica Acta, Vol. 627, Issue 1
HMDB: the Human Metabolome Database
journal, January 2007
- Wishart, D. S.; Tzur, D.; Knox, C.
- Nucleic Acids Research, Vol. 35, Issue Database
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
Internal energy and fragmentation of ions produced in electrospray sources
journal, January 2005
- Gabelica, Valérie; Pauw, Edwin De
- Mass Spectrometry Reviews, Vol. 24, Issue 4
Avoiding Misannotation of In-Source Fragmentation Products as Cellular Metabolites in Liquid Chromatography–Mass Spectrometry-Based Metabolomics
journal, January 2015
- Xu, Yi-Fan; Lu, Wenyun; Rabinowitz, Joshua D.
- Analytical Chemistry, Vol. 87, Issue 4
An accelerated workflow for untargeted metabolomics using the METLIN database
journal, September 2012
- Tautenhahn, Ralf; Cho, Kevin; Uritboonthai, Winnie
- Nature Biotechnology, Vol. 30, Issue 9
LIPID MAPS online tools for lipid research
journal, May 2007
- Fahy, E.; Sud, M.; Cotter, D.
- Nucleic Acids Research, Vol. 35, Issue Web Server
YMDB: the Yeast Metabolome Database
journal, November 2011
- Jewison, T.; Knox, C.; Neveu, V.
- Nucleic Acids Research, Vol. 40, Issue D1
ECMDB: The E. coli Metabolome Database
journal, October 2012
- Guo, An Chi; Jewison, Timothy; Wilson, Michael
- Nucleic Acids Research, Vol. 41, Issue D1
Absolute metabolite concentrations and implied enzyme active site occupancy in Escherichia coli
journal, June 2009
- Bennett, Bryson D.; Kimball, Elizabeth H.; Gao, Melissa
- Nature Chemical Biology, Vol. 5, Issue 8
Glucose feeds the TCA cycle via circulating lactate
journal, October 2017
- Hui, Sheng; Ghergurovich, Jonathan M.; Morscher, Raphael J.
- Nature, Vol. 551, Issue 7678
Noninvasive liquid diet delivery of stable isotopes into mouse models for deep metabolic network tracing
journal, November 2017
- Sun, Ramon C.; Fan, Teresa W. -M.; Deng, Pan
- Nature Communications, Vol. 8, Issue 1
Lactate Metabolism in Human Lung Tumors
journal, October 2017
- Faubert, Brandon; Li, Kevin Y.; Cai, Ling
- Cell, Vol. 171, Issue 2
Metabolomics and Isotope Tracing
journal, May 2018
- Jang, Cholsoon; Chen, Li; Rabinowitz, Joshua D.
- Cell, Vol. 173, Issue 4
Works referencing / citing this record:
CROP: correlation-based reduction of feature multiplicities in untargeted metabolomic data
journal, January 2020
- Kouřil, Štěpán; de Sousa, Julie; Václavík, Jan
- Bioinformatics, Vol. 36, Issue 9
Elevated Choline Kinase α–Mediated Choline Metabolism Supports the Prolonged Survival of TRAF3-Deficient B Lymphocytes
journal, December 2019
- Gokhale, Samantha; Lu, Wenyun; Zhu, Sining
- The Journal of Immunology, Vol. 204, Issue 2
Deep annotation of untargeted LC-MS metabolomics data with Binner
journal, October 2019
- Kachman, Maureen; Habra, Hani; Duren, William
- Bioinformatics
Untargeted metabolomics links glutathione to bacterial cell cycle progression
journal, February 2020
- Hartl, Johannes; Kiefer, Patrick; Kaczmarczyk, Andreas
- Nature Metabolism, Vol. 2, Issue 2