Emerging new strategies for successful metabolite identification in metabolomics

Papers of special note have been highlighted as: • of interest

References

• 1 Nicholson JK, Wilson ID. Understanding ‘global’ systems biology: metabonomics and the continuum of metabolism. Nat. Rev. Drug Discov. 2, 668–676 (2003).
  Medline CASGoogle Scholar
• 2 Nicholson JK, Holmes E, Lindon JC, Wilson ID. The challenges of modeling mammalian biocomplexity. Nat. Biotechnol. 22, 1268–1274 (2004).
  Medline CASGoogle Scholar
• 3 Fiehn O. Combining genomics, metabolome analysis, and biochemical modelling to understand metabolic networks. Comp. Funct. Genomics 2, 155–168 (2001).
  Medline CASGoogle Scholar
• 4 Nicholson JK, Connelly J, Lindon JC, Holmes E. Metabonomics: a platform for studying drug toxicity and gene function. Nat. Rev. Drug Discov. 1, 153–161 (2002).
  Medline CASGoogle Scholar
• 5 Fan TW, Lane AN. NMR-based stable isotope resolved metabolomics in systems biochemistry. J. Biomol. NMR 49, 267–280 (2011).
  Medline CASGoogle Scholar
• 6 Raamsdonk LM, Teusink B, Broadhurst D et al. A functional genomics strategy that uses metabolome data to reveal the phenotype of silent mutations. Nat. Biotechnol. 19, 45–50 (2001).
  Medline CASGoogle Scholar
• 7 Holmes E, Wilson ID, Nicholson JK. Metabolic phenotyping in health and disease. Cell 134, 714–717 (2008).
  Medline CASGoogle Scholar
• 8 Powers R. The current state of drug discovery and a potential role for NMR metabolomics. J. Med. Chem. 57, 5860–5870 (2014).
  Medline CASGoogle Scholar
• 9 Scalbert A, Brennan L, Manach C et al. The food metabolome: a window over dietary exposure. Am. J. Clin. Nutr. 99, 1286–1308 (2014).
  Medline CASGoogle Scholar
• 10 Nicholson JK, Lindon JC. Systems biology: metabonomics. Nature 455, 1054–1056 (2008).
  Medline CASGoogle Scholar
• 11 Dunn WB, Broadhurst DI, Atherton HJ, Goodacre R, Griffin JL. Systems level studies of mammalian metabolomes: the roles of mass spectrometry and nuclear magnetic resonance spectroscopy. Chem. Soc. Rev. 40, 387–426 (2011).
  Medline CASGoogle Scholar
• 12 Palmnas MS, Vogel HJ. The future of NMR metabolomics in cancer therapy: towards personalizing treatment and developing targeted drugs? Metabolites 3, 373–396 (2013).
  Medline CASGoogle Scholar
• 13 Emwas AH, Luchinat C, Turano P et al. Standardizing the experimental conditions for using urine in NMR-based metabolomic studies with a particular focus on diagnostic studies: a review. Metabolomics 11, 872–894 (2015).
  Medline CASGoogle Scholar
• 14 Beckonert O, Keun HC, Ebbels TM et al. Metabolic profiling, metabolomic and metabonomic procedures for NMR spectroscopy of urine, plasma, serum and tissue extracts. Nat. Protoc. 2, 2692–2703 (2007).
  Medline CASGoogle Scholar
• 15 Kim HK, Choi YH, Verpoorte R. NMR-based metabolomic analysis of plants. Nat. Protoc. 5, 536–549 (2010).
  Medline CASGoogle Scholar
• 16 Dona AC, Jimenez B, Schafer H et al. Precision high-throughput proton NMR spectroscopy of human urine, serum, and plasma for large-scale metabolic phenotyping. Anal. Chem. 86, 9887–9894 (2014).
  Medline CASGoogle Scholar
• 17 Brindle JT, Antti H, Holmes E et al. Rapid and noninvasive diagnosis of the presence and severity of coronary heart disease using 1H-NMR-based metabonomics. Nat. Med. 8, 1439–1444 (2002).
  Medline CASGoogle Scholar
• 18 Gowda GA, Zhang S, Gu H, Asiago V, Shanaiah N, Raftery D. Metabolomics-based methods for early disease diagnostics. Expert Rev. Mol. Diagn. 8, 617–633 (2008).
  Medline CASGoogle Scholar
• 19 Duarte IF, Diaz SO, Gil AM. NMR metabolomics of human blood and urine in disease research. J. Pharm. Biomed. Anal. 93, 17–26 (2014).
  Medline CASGoogle Scholar
• 20 Clayton TA, Lindon JC, Cloarec O et al. Pharmaco-metabonomic phenotyping and personalized drug treatment. Nature 440, 1073–1077 (2006).
  Medline CASGoogle Scholar
• 21 Ramautar R, Berger R, Van Der Greef J, Hankemeier T. Human metabolomics: strategies to understand biology. Curr. Opin. Chem. Biol. 17, 841–846 (2013).
  Medline CASGoogle Scholar
• 22 Nicholson JK, Holmes E, Kinross JM, Darzi AW, Takats Z, Lindon JC. Metabolic phenotyping in clinical and surgical environments. Nature 491, 384–392 (2012).
  Medline CASGoogle Scholar
• 23 Lindon JC, Nicholson JK. The emergent role of metabolic phenotyping in dynamic patient stratification. Expert Opin. Drug Metab. Toxicol. 10, 915–919 (2014).
  Medline CASGoogle Scholar
• 24 Bingol K, Brüschweiler R. Two elephants in the room: new hybrid nuclear magnetic resonance and mass spectrometry approaches for metabolomics. Curr. Opin. Clin. Nutr. Metab. Care 18, 471–477 (2015).
  Medline CASGoogle Scholar
• 25 Gowda GA, Raftery D. Can NMR solve some significant challenges in metabolomics. J. Magn. Reson. 260, 144–160 (2015).
  MedlineGoogle Scholar
• 26 Bingol K, Salinas RK, Brüschweiler R. Higher-rank correlation NMR spectra with spectral moment filtering. J. Phys. Chem. Lett. 1, 1086–1089 (2010).
  Medline CASGoogle Scholar
• 27 Bingol K, Brüschweiler R. Deconvolution of chemical mixtures with high complexity by NMR consensus trace clustering. Anal. Chem. 83, 7412–7417 (2011).
  Medline CASGoogle Scholar
• 28 Hubert J, Nuzillard JM, Purson S et al. Identification of natural metabolites in mixture: a pattern recognition strategy based on 13C NMR. Anal. Chem. 86, 2955–2962 (2014).
  Medline CASGoogle Scholar
• 29 Wishart DS. Advances in metabolite identification. Bioanalysis 3, 1769–1782 (2011).
  CASGoogle Scholar
• 30 Halabalaki M, Vougogiannopoulou K, Mikros E, Skaltsounis AL. Recent advances and new strategies in the NMR-based identification of natural products. Curr. Opin. Biotechnol. 25, 1–7 (2014).
  Medline CASGoogle Scholar
• 31 Bingol K, Zhang F, Bruschweiler-Li L, Brüschweiler R. TOCCATA: a customized carbon total correlation spectroscopy NMR metabolomics database. Anal. Chem. 84, 9395–9401 (2012).
  Medline CASGoogle Scholar
• 32 Bingol K, Bruschweiler-Li L, Li DW, Brüschweiler R. Customized metabolomics database for the analysis of NMR 1H-1H TOCSY and 13C-1H HSQC-TOCSY spectra of complex mixtures. Anal. Chem. 86, 5494–5501 (2014). • Presents the first customized 2D 1H-1H TOCSY and 2D 13C-1H HSQC-TOCSY metabolomics database and query, which significantly improved the accuracy of metabolite identification. The web server is open to the public at [61].
  Medline CASGoogle Scholar
• 33 Bingol K, Li DW, Bruschweiler-Li L et al. Unified and isomer-specific NMR metabolomics database for the accurate analysis of 13C-1H HSQC spectra. ACS Chem. Biol. 10, 452–459 (2015). • Presents the first unified and customized 2D 13C-1H HSQC metabolomics database and query, which significantly improved the accuracy of metabolite identification. The web server is open to the public at [62].
  Medline CASGoogle Scholar
• 34 Ellinger JJ, Chylla RA, Ulrich EL, Markley JL. Databases and software for NMR-based metabolomics. Curr. Metabol. 1, 28–40 (2013).
  CASGoogle Scholar
• 35 Alonso A, Marsal S, Julia A. Analytical methods in untargeted metabolomics: state of the art in 2015. Front. Bioeng. Biotechnol. 3, 23 (2015).
  MedlineGoogle Scholar
• 36 Qiu F, Mcalpine JB, Lankin DC et al. 2D NMR barcoding and differential analysis of complex mixtures for chemical identification: the Actaea triterpenes. Anal. Chem. 86, 3964–3972 (2014).
  Medline CASGoogle Scholar
• 37 Clendinen CS, Pasquel C, Ajredini R, Edison AS. 13C NMR metabolomics: INADEQUATE network analysis. Anal. Chem. 87, 5698–5706 (2015).
  Medline CASGoogle Scholar
• 38 Pan Z, Raftery D. Comparing and combining NMR spectroscopy and mass spectrometry in metabolomics. Anal. Bioanal. Chem. 387, 525–527 (2007).
  Medline CASGoogle Scholar
• 39 Crockford DJ, Holmes E, Lindon JC et al. Statistical heterospectroscopy, an approach to the integrated analysis of NMR and UPLC-MS data sets: application in metabonomic toxicology studies. Anal. Chem. 78, 363–371 (2006).
  Medline CASGoogle Scholar
• 40 Pan Z, Gu H, Talaty N et al. Principal component analysis of urine metabolites detected by NMR and DESI-MS in patients with inborn errors of metabolism. Anal. Bioanal. Chem. 387, 539–549 (2007).
  Medline CASGoogle Scholar
• 41 Crockford DJ, Maher AD, Ahmadi KR et al. 1H NMR and UPLC-MS(E) statistical heterospectroscopy: characterization of drug metabolites (xenometabolome) in epidemiological studies. Anal. Chem. 80, 6835–6844 (2008).
  Medline CASGoogle Scholar
• 42 Fan TW, Lorkiewicz PK, Sellers K, Moseley HN, Higashi RM, Lane AN. Stable isotope-resolved metabolomics and applications for drug development. Pharmacol. Ther. 133, 366–391 (2012).
  Medline CASGoogle Scholar
• 43 Clendinen CS, Stupp GS, Ajredini R, Lee-Mcmullen B, Beecher C, Edison AS. An overview of methods using 13C for improved compound identification in metabolomics and natural products. Front. Plant Sci. 6, 611 (2015).
  MedlineGoogle Scholar
• 44 Marshall DD, Lei S, Worley B et al. Combining DI-ESI-MS and NMR datasets for metabolic profiling. Metabolomics 11, 391–402 (2015).
  Medline CASGoogle Scholar
• 45 Dame ZT, Aziat F, Mandal R et al. The human saliva metabolome. Metabolomics 11, 1864–1883 (2015).
  CASGoogle Scholar
• 46 Holmes E, Loo RL, Stamler J et al. Human metabolic phenotype diversity and its association with diet and blood pressure. Nature 453, 396–400 (2008).
  Medline CASGoogle Scholar
• 47 Suhre K, Wallaschofski H, Raffler J et al. A genome-wide association study of metabolic traits in human urine. Nat. Genet. 43, 565–569 (2011).
  Medline CASGoogle Scholar
• 48 Clendinen CS, Lee-Mcmullen B, Williams CM et al. 13C NMR metabolomics: applications at natural abundance. Anal. Chem. 86, 9242–9250 (2014).
  Medline CASGoogle Scholar
• 49 Bingol K, Brüschweiler R. Multidimensional approaches to NMR-based metabolomics. Anal. Chem. 86, 47–57 (2014).
  Medline CASGoogle Scholar
• 50 Bingol K, Zhang F, Bruschweiler-Li L, Brüschweiler R. Quantitative analysis of metabolic mixtures by two-dimensional 13C constant-time TOCSY NMR spectroscopy. Anal. Chem. 85, 6414–6420 (2013).
  Medline CASGoogle Scholar
• 51 Bodenhausen G, Ruben DJ. Natural abundance N-15 NMR by enhanced heteronuclear spectroscopy. Chem. Phys. Lett. 69, 185–189 (1980).
  CASGoogle Scholar
• 52 Braunschweiler L, Ernst RR. Coherence transfer by isotropic mixing - application to proton correlation spectroscopy. J. Magn. Reson. 53, 521–528 (1983).
  CASGoogle Scholar
• 53 Saric J, Wang Y, Li J et al. Species variation in the fecal metabolome gives insight into differential gastrointestinal function. J. Proteome Res. 7, 352–360 (2008).
  Medline CASGoogle Scholar
• 54 Misawa T, Date Y, Kikuchi J. Human metabolic, mineral, and microbiota fluctuations across daily nutritional intake visualized by a data-driven approach. J. Proteome Res. 14, 1526–1534 (2015).
  Medline CASGoogle Scholar
• 55 Gronwald W, Klein MS, Zeltner R et al. Detection of autosomal dominant polycystic kidney disease by NMR spectroscopic fingerprinting of urine. Kidney Int. 79, 1244–1253 (2011).
  Medline CASGoogle Scholar
• 56 Guennec AL, Giraudeau P, Caldarelli S. Evaluation of fast 2D NMR for metabolomics. Anal. Chem. 86, 5946–5954 (2014).
  Medline CASGoogle Scholar
• 57 Wen H, An YJ, Xu WJ, Kang KW, Park S. Real-time monitoring of cancer cell metabolism and effects of an anticancer agent using 2D in-cell NMR spectroscopy. Angew. Chem. Int. Ed. 54, 5374–5377 (2015).
  Medline CASGoogle Scholar
• 58 Motta A, Paris D, Melck D. Monitoring real-time metabolism of living cells by fast two-dimensional NMR spectroscopy. Anal. Chem. 82, 2405–2411 (2010).
  Medline CASGoogle Scholar
• 59 Martineau E, Giraudeau P, Tea I, Akoka S. Fast and precise quantitative analysis of metabolic mixtures by 2D 1H INADEQUATE NMR. J. Pharm. Biomed. Anal. 54, 252–257 (2011).
  Medline CASGoogle Scholar
• 60 COLMAR ¹³C-TOCCATA: a Carbon TOCSY NMR Metabolomics Database. http://spin.ccic.ohio-state.edu/index.php/toccata/index.
  Google Scholar
• 61 COLMAR ¹H(¹³C)-TOCCATA: Customized Metabolomics Database for the Analysis of NMR ¹H-¹H TOCSY and ¹³C-¹H HSQC-TOCSY Spectra of Complex Mixtures. http://spin.ccic.ohio-state.edu/index.php/toccata2/index.
  Google Scholar
• 62 COLMAR ¹³C-¹H HSQC Query. http://spin.ccic.ohio-state.edu/index.php/hsqc/index.
  Google Scholar
• 63 Ulrich EL, Akutsu H, Doreleijers JF et al. BioMagResBank. Nucleic Acids Res. 36, D402–D408 (2008).
  Medline CASGoogle Scholar
• 64 Biological Magnetic Resonance Data Bank. www.bmrb.wisc.edu.
  Google Scholar
• 65 Wishart DS, Jewison T, Guo AC et al. HMDB 3.0-The Human Metabolome Database in 2013. Nucleic Acids Res. 41, D801–D807 (2013).
  Medline CASGoogle Scholar
• 66 The Human Metabolome Database. www.hmdb.ca.
  Google Scholar
• 67 Kikuchi J, Tsuboi Y, Komatsu K, Gomi M, Chikayama E, Date Y. SpinCouple: development of a web tool for analyzing metabolite mixtures via two-dimensional J-resolved NMR database. Anal. Chem. 88, 659–665 (2016).
  Medline CASGoogle Scholar
• 68 SpinCouple. http://emar.riken.jp/spincpl.
  Google Scholar
• 69 Aue WP, Karhan J, Ernst RR. Homonuclear broad-band decoupling and 2-dimensional J-resolved NMR-spectroscopy. J. Chem. Phys. 64, 4226–4227 (1976).
  CASGoogle Scholar
• 70 Birmingham Metabolite Library. www.bml-nmr.org.
  Google Scholar
• 71 Ludwig C, Easton JM, Lodi A et al. Birmingham Metabolite Library: a publicly accessible database of 1D 1H and 2D 1H J-resolved NMR spectra of authentic metabolite standards (BML-NMR). Metabolomics 8, 8–18 (2012).
  CASGoogle Scholar
• 72 Fonville JM, Maher AD, Coen M, Holmes E, Lindon JC, Nicholson JK. Evaluation of full-resolution J-resolved 1H NMR projections of biofluids for metabonomics information retrieval and biomarker identification. Anal. Chem. 82, 1811–1821 (2010).
  Medline CASGoogle Scholar
• 73 Psychogios N, Hau DD, Peng J et al. The human serum metabolome. PLoS ONE 6, e16957 (2011).
  Medline CASGoogle Scholar
• 74 Bouatra S, Aziat F, Mandal R et al. The human urine metabolome. PLoS ONE 8, e73076 (2013).
  Medline CASGoogle Scholar
• 75 Bingol K, Brüschweiler R. NMR/MS Translator for the enhanced simultaneous analysis of metabolomics mixtures by NMR spectroscopy and mass spectrometry: application to human urine. J. Proteome Res. 14, 2642–2648 (2015). • Presents a combined NMR/MS approach that provides rapid and accurate identification of cataloged, in other words, known metabolites detected in both NMR and MS spectra of the same metabolomic sample.
  Medline CASGoogle Scholar
• 76 Bingol K, Bruschweiler-Li L, Yu C, Somogyi A, Zhang F, Brüschweiler R. Metabolomics beyond spectroscopic databases: a combined MS/NMR strategy for the rapid identification of new metabolites in complex mixtures. Anal. Chem. 87, 3864–3870 (2015). • Introduces a combined NMR/MS approach that allows structure elucidation of unknown metabolites in complex metabolite mixtures. The approach does not require purifications of unknown compounds from the matrix, therefore it provides a platform with the potential for high-throughput discovery of new metabolites.
  Medline CASGoogle Scholar
• 77 Madison Metabolomics Consortium Database. http://mmcd.nmrfam.wisc.edu.
  Google Scholar
• 78 Cui Q, Lewis IA, Hegeman AD et al. Metabolite identification via the Madison Metabolomics Consortium Database. Nat. Biotechnol. 26, 162–164 (2008).
  Medline CASGoogle Scholar
• 79 COLMAR. http://spin.ccic.ohio-state.edu/index.php/colmar.
  Google Scholar
• 80 Koehn FE, Carter GT. The evolving role of natural products in drug discovery. Nat. Rev. Drug Discov. 4, 206–220 (2005).
  Medline CASGoogle Scholar
• 81 Bingol K, Zhang F, Bruschweiler-Li L, Brüschweiler R. Carbon backbone topology of the metabolome of a cell. J. Am. Chem. Soc. 134, 9006–9011 (2012).
  Medline CASGoogle Scholar
• 82 ChemSpider. www.chemspider.com.
  Google Scholar
• 83 Pence HE, Williams A. ChemSpider: an online chemical information resource. J. Chem. Educ. 87, 1123–1124 (2010).
  CASGoogle Scholar
• 84 Scripps Center for Metabolomics. https://metlin.scripps.edu/index.php.
  Google Scholar
• 85 Zhu ZJ, Schultz AW, Wang J et al. Liquid chromatography quadrupole time-of-flight mass spectrometry characterization of metabolites guided by the METLIN database. Nat. Protocols 8, 451–460 (2013).
  Medline CASGoogle Scholar
• 86 Willoughby PH, Jansma MJ, Hoye TR. A guide to small-molecule structure assignment through computation of 1H and 13C NMR chemical shifts. Nat. Protoc. 9, 643–660 (2014).
  Medline CASGoogle Scholar
• 87 Tayyari F, Gowda GA, Gu H, Raftery D. 15N-cholamine- a smart isotope tag for combining NMR- and MS-based metabolite profiling. Anal. Chem. 85, 8715–8721 (2013). • Introduces 15N-cholamine tag to facilitate detection of carboxyl group containing metabolites in NMR and MS spectra of human serum and urine.
  Medline CASGoogle Scholar
• 88 Lane AN, Arumugam S, Lorkiewicz PK et al. Chemoselective detection and discrimination of carbonyl-containing compounds in metabolite mixtures by 1H-detected 15N nuclear magnetic resonance. Magn. Reson. Chem. 53, 337–343 (2015). • Introduces 15N-labeled aminooxy probes to facilitate detection of carbonyl group containing metabolites in NMR and MS spectra of lung adenocarcinoma cell line.
  Medline CASGoogle Scholar
• 89 Fernandez-Megia E, Correa J, Novoa-Carballal R, Riguera R. Paramagnetic NMR relaxation in polymeric matrixes: sensitivity enhancement and selective suppression of embedded species (1H and 13C PSR filter). J. Am. Chem. Soc. 129, 15164–15173 (2007).
  Medline CASGoogle Scholar
• 90 Correa J, Pinto LF, Riguera R, Fernandez-Megia E. Predicting PSR filters by transverse relaxation enhancements. Anal. Chem. 87, 760–767 (2015). • Combines paramagnetic relaxation agent, gadolinium, with CPMG NMR spectroscopy to selectively filter components in mixtures based on their complexing ability with gadolinium.
  Medline CASGoogle Scholar
• 91 Gowda GAN, Raftery D. Quantitating metabolites in protein precipitated serum using NMR spectroscopy. Anal. Chem. 86, 5433–5440 (2014).
  Medline CASGoogle Scholar
• 92 Zhang B, Xie M, Bruschweiler-Li L, Bingol K, Brüschweiler R. Use of charged nanoparticles in NMR-based metabolomics for spectral simplification and improved metabolite identification. Anal. Chem. 87, 7211–7217 (2015). • Introduces electrically charged silica nanoparticles as chemical agents to differentiate mixture components in NMR spectra based on their electric charge.
  Medline CASGoogle Scholar