Metabolomics

Metabolomics is the scientific study of chemical processes involving metabolites, the small molecule
substrates, intermediates, and products of cell metabolism. Specifically, metabolomics is the
"systematic study of the unique chemical fingerprints that specific cellular processes leave behind",
the study of their small-molecule metabolite profiles.[1] The metabolome represents the complete set
of metabolites in a biological cell, tissue, organ, or organism, which are the end products of cellular
processes.[2] Messenger RNA (mRNA), gene expression data, and proteomic analyses reveal the set
of gene products being produced in the cell, data that represents one aspect of cellular function.
Conversely, metabolic profiling can give an instantaneous snapshot of the physiology of that cell,[3]
and thus, metabolomics provides a direct "functional readout of the physiological state" of an
organism.[4] There are indeed quantifiable correlations between the metabolome and the other cellular
The central dogma of biology
ensembles (genome, transcriptome, proteome, and lipidome), which can be used to predict metabolite
showing the flow of information from
abundances in biological samples from, for example mRNA abundances.[5] One of the ultimate
DNA to the phenotype. Associated
challenges of systems biology is to integrate metabolomics with all other -omics information to with each stage is the corresponding
provide a better understanding of cellular biology.
systems biology tool, from genomics
to metabolomics.
History
The concept that individuals might have a "metabolic profile" that could be reflected in the makeup of their biological fluids was introduced
by Roger Williams in the late 1940s,[6] who used paper chromatography to suggest characteristic metabolic patterns in urine and saliva were
associated with diseases such as schizophrenia. However, it was only through technological advancements in the 1960s and 1970s that it
became feasible to quantitatively (as opposed to qualitatively) measure metabolic profiles.[7] The term "metabolic profile" was introduced by
Horning, et al. in 1971 after they demonstrated that gas chromatography-mass spectrometry (GC-MS) could be used to measure compounds
present in human urine and tissue extracts.[8][9] The Horning group, along with that of Linus Pauling and Arthur B. Robinson led the
development of GC-MS methods to monitor the metabolites present in urine through the 1970s.[10]

Concurrently, NMR spectroscopy, which was discovered in the 1940s, was also undergoing rapid advances. In 1974, Seeley et al.
demonstrated the utility of using NMR to detect metabolites in unmodified biological samples.[11] This first study on muscle highlighted the
value of NMR in that it was determined that 90% of cellular ATP is complexed with magnesium. As sensitivity has improved with the
evolution of higher magnetic field strengths and magic angle spinning, NMR continues to be a leading analytical tool to investigate
metabolism.[8][12] Recent efforts to utilize NMR for metabolomics have been largely driven by the laboratory of Jeremy K. Nicholson at
Birkbeck College, University of London and later at Imperial College London. In 1984, Nicholson showed 1 H NMR spectroscopy could
potentially be used to diagnose diabetes mellitus, and later pioneered the application of pattern recognition methods to NMR spectroscopic
data.[13][14]

In 1994 and 1996 liquid chromatography mass spectrometry metabolomics experiments[15][16] were performed by Gary Siuzdak while
working with Richard Lerner (then president of The Scripps Research Institute) and Benjamin Cravatt, to analyze the cerebral spinal fluid
from sleep deprived animals. One molecule of particular interest, oleamide, was observed and later shown to have sleep inducing properties.
This work is one of the earliest such experiments combining liquid chromatography and mass spectrometry in metabolomics.

In 2005, the first metabolomics tandem mass spectrometry database, METLIN,[17][18] for characterizing human metabolites was developed
in the Siuzdak laboratory at The Scripps Research Institute. METLIN has since grown and as of July 1, 2019, METLIN contains over
450,000 metabolites and other chemical entities, each compound having experimental tandem mass spectrometry data generated from
molecular standards at multiple collision energies and in positive and negative ionization modes. METLIN is the largest repository of tandem
mass spectrometry data of its kind. The dedicated academic journal Metabolomics first appeared in 2005, founded by its current editor-in-
chief Roy Goodacre.

In 2005, the Siuzdak lab was engaged in identifying metabolites associated with sepsis and in an effort to address the issue of statistically
identifying the most relevant dysregulated metabolites across hundreds of LC/MS datasets, the first algorithm was developed to allow for the
nonlinear alignment of mass spectrometry metabolomics data. Called XCMS,[19] it has since (2012)[20] been developed as an online tool and
as of 2019 (with METLIN) has over 30,000 registered users.

On 23 January 2007, the Human Metabolome Project, led by David S. Wishart, completed the first draft of the human metabolome,
consisting of a database of approximately 2,500 metabolites, 1,200 drugs and 3,500 food components.[21][22] Similar projects have been
underway in several plant species, most notably Medicago truncatula[23] and Arabidopsis thaliana[24] for several years.

As late as mid-2010, metabolomics was still considered an "emerging field".[25] Further, it was noted that further progress in the field
depended in large part, through addressing otherwise "irresolvable technical challenges", by technical evolution of mass spectrometry
instrumentation.[25]
In 2015, real-time metabolome profiling was demonstrated for the first time.[26]

Metabolome
The metabolome refers to the complete set of small-molecule (<1.5 kDa)[21] metabolites (such as
metabolic intermediates, hormones and other signaling molecules, and secondary metabolites) to be
found within a biological sample, such as a single organism.[27][28] The word was coined in analogy
with transcriptomics and proteomics; like the transcriptome and the proteome, the metabolome is
dynamic, changing from second to second. Although the metabolome can be defined readily enough,
it is not currently possible to analyse the entire range of metabolites by a single analytical method.

The first metabolite database (called METLIN) for searching fragmentation data from tandem mass
spectrometry experiments was developed by the Siuzdak lab at The Scripps Research Institute in
2005.[17][18] METLIN contains over 450,000 metabolites and other chemical entities, each
compound having experimental tandem mass spectrometry data. In 2006,[19] the Siuzdak lab also
developed the first algorithm to allow for the nonlinear alignment of mass spectrometry metabolomics Human metabolome project
data. Called XCMS, where the "X" constitutes any chromatographic technology, it has been
developed as an online tool.

In January 2007, scientists at the University of Alberta and the University of Calgary completed the first draft of the human metabolome. The
Human Metabolome Database (HMDB) is perhaps the most extensive public metabolomic spectral database to date[29] and is a freely
available electronic database (www.hmdb.ca) containing detailed information about small molecule metabolites found in the human body. It
is intended to be used for applications in metabolomics, clinical chemistry, biomarker discovery and general education. The database is
designed to contain or link three kinds of data:

1. Chemical data,
2. Clinical data and
3. Molecular biology/biochemistry data.

The database contains 220,945 metabolite entries including both water-soluble and lipid soluble metabolites. Additionally, 8,610 protein
sequences (enzymes and transporters) are linked to these metabolite entries. Each MetaboCard entry contains 130 data fields with 2/3 of the
information being devoted to chemical/clinical data and the other 1/3 devoted to enzymatic or biochemical data.[30] The version 3.5 of the
HMDB contains >16,000 endogenous metabolites, >1,500 drugs and >22,000 food constituents or food metabolites.[31] This information,
available at the Human Metabolome Database and based on analysis of information available in the current scientific literature, is far from
complete.[32] In contrast, much more is known about the metabolomes of other organisms. For example, over 50,000 metabolites have been
characterized from the plant kingdom, and many thousands of metabolites have been identified and/or characterized from single
plants.[33][34]

Each type of cell and tissue has a unique metabolic ‘fingerprint’ that can elucidate organ or tissue-specific information. Bio-specimens used
for metabolomics analysis include but not limit to plasma, serum, urine, saliva, feces, muscle, sweat, exhaled breath and gastrointestinal
fluid.[35] The ease of collection facilitates high temporal resolution, and because they are always at dynamic equilibrium with the body, they
can describe the host as a whole.[36] Genome can tell what could happen, transcriptome can tell what appears to be happening, proteome can
tell what makes it happen and metabolome can tell what has happened and what is happening.[37]

Metabolites
Metabolites are the substrates, intermediates and products of metabolism. Within the context of metabolomics, a metabolite is usually defined
as any molecule less than 1.5 kDa in size.[21] However, there are exceptions to this depending on the sample and detection method. For
example, macromolecules such as lipoproteins and albumin are reliably detected in NMR-based metabolomics studies of blood plasma.[38] In
plant-based metabolomics, it is common to refer to "primary" and "secondary" metabolites.[3] A primary metabolite is directly involved in the
normal growth, development, and reproduction. A secondary metabolite is not directly involved in those processes, but usually has important
ecological function. Examples include antibiotics and pigments.[39] By contrast, in human-based metabolomics, it is more common to
describe metabolites as being either endogenous (produced by the host organism) or exogenous.[40][41] Metabolites of foreign substances
such as drugs are termed xenometabolites.[42]

The metabolome forms a large network of metabolic reactions, where outputs from one enzymatic chemical reaction are inputs to other
chemical reactions. Such systems have been described as hypercycles.

Metabonomics
Metabonomics is defined as "the quantitative measurement of the dynamic multiparametric metabolic response of living systems to
pathophysiological stimuli or genetic modification". The word origin is from the Greek μεταβολή meaning change and nomos meaning a rule
set or set of laws.[43] This approach was pioneered by Jeremy Nicholson at Murdoch University and has been used in toxicology, disease
diagnosis and a number of other fields. Historically, the metabonomics approach was one of the first methods to apply the scope of systems
biology to studies of metabolism.[44][45][46]
There has been some disagreement over the exact differences between 'metabolomics' and 'metabonomics'. The difference between the two
terms is not related to choice of analytical platform: although metabonomics is more associated with NMR spectroscopy and metabolomics
with mass spectrometry-based techniques, this is simply because of usages amongst different groups that have popularized the different
terms. While there is still no absolute agreement, there is a growing consensus that 'metabolomics' places a greater emphasis on metabolic
profiling at a cellular or organ level and is primarily concerned with normal endogenous metabolism. 'Metabonomics' extends metabolic
profiling to include information about perturbations of metabolism caused by environmental factors (including diet and toxins), disease
processes, and the involvement of extragenomic influences, such as gut microflora. This is not a trivial difference; metabolomic studies
should, by definition, exclude metabolic contributions from extragenomic sources, because these are external to the system being studied.
However, in practice, within the field of human disease research there is still a large degree of overlap in the way both terms are used, and
they are often in effect synonymous.[47]

Exometabolomics
Exometabolomics, or "metabolic footprinting", is the study of extracellular metabolites. It uses many techniques from other subfields of
metabolomics, and has applications in biofuel development, bioprocessing, determining drugs' mechanism of action, and studying
intercellular interactions.[48]

Analytical technologies
The typical workflow of metabolomics studies is shown in the figure. First, samples are collected
from tissue, plasma, urine, saliva, cells, etc. Next, metabolites extracted often with the addition of
internal standards and derivatization.[49] During sample analysis, metabolites are quantified (liquid
chromatography or gas chromatography coupled with MS and/or NMR spectroscopy). The raw
output data can be used for metabolite feature extraction and further processed before statistical
analysis (such as PCA). Many bioinformatic tools and software are available to identify associations
with disease states and outcomes, determine significant correlations, and characterize metabolic
signatures with existing biological knowledge.[50]

Separation methods

Initially, analytes in a metabolomic sample comprise a highly complex mixture. This complex mixture
can be simplified prior to detection by separating some analytes from others. Separation achieves
various goals: analytes which cannot be resolved by the detector may be separated in this step; in MS
analysis, ion suppression is reduced; the retention time of the analyte serves as information regarding
its identity. This separation step is not mandatory and is often omitted in NMR and "shotgun" based Key stages of a metabolomics study
approaches such as shotgun lipidomics.

Gas chromatography (GC), especially when interfaced with mass spectrometry (GC-MS), is a widely used separation technique for
metabolomic analysis. GC offers very high chromatographic resolution, and can be used in conjunction with a flame ionization detector
(GC/FID) or a mass spectrometer (GC-MS). The method is especially useful for identification and quantification of small and volatile
molecules.[51] However, a practical limitation of GC is the requirement of chemical derivatization for many biomolecules as only volatile
chemicals can be analysed without derivatization. In cases where greater resolving power is required, two-dimensional chromatography
(GCxGC) can be applied.

High performance liquid chromatography (HPLC) has emerged as the most common separation technique for metabolomic analysis. With
the advent of electrospray ionization, HPLC was coupled to MS. In contrast with GC, HPLC has lower chromatographic resolution, but
requires no derivatization for polar molecules, and separates molecules in the liquid phase. Additionally HPLC has the advantage that a much
wider range of analytes can be measured with a higher sensitivity than GC methods.[52]

Capillary electrophoresis (CE) has a higher theoretical separation efficiency than HPLC (although requiring much more time per separation),
and is suitable for use with a wider range of metabolite classes than is GC. As for all electrophoretic techniques, it is most appropriate for
charged analytes.[53]

Detection methods

Mass spectrometry (MS) is used to identify and quantify metabolites after optional separation by GC, HPLC, or CE. GC-MS was the first
hyphenated technique to be developed. Identification leverages the distinct patterns in which analytes fragment. These patterns can be
thought of as a mass spectral fingerprint. Libraries exist that allow identification of a metabolite according to this fragmentation pattern. MS is
both sensitive and can be very specific. There are also a number of techniques which use MS as a stand-alone technology: the sample is
infused directly into the mass spectrometer with no prior separation, and the MS provides sufficient selectivity to both separate and to detect
metabolites.

For analysis by mass spectrometry, the analytes must be imparted with a charge and transferred to the gas phase. Electron ionization (EI) is
the most common ionization technique applied to GC separations as it is amenable to low pressures. EI also produces fragmentation of the
analyte, both providing structural information while increasing the complexity of the data and possibly obscuring the molecular ion.
Atmospheric-pressure chemical ionization (APCI) is an atmospheric pressure technique that can be applied to all the above separation
techniques. APCI is a gas phase ionization method, which provides slightly more aggressive ionization than ESI which is suitable for less
polar compounds. Electrospray ionization (ESI) is the most common ionization technique applied in LC/MS. This soft ionization is most
successful for polar molecules with ionizable functional groups. Another commonly used soft ionization technique is secondary electrospray
ionization (SESI).

In the 2000s, surface-based mass analysis has seen a resurgence, with new MS technologies focused on increasing sensitivity, minimizing
background, and reducing sample preparation. The ability to analyze metabolites directly from biofluids and tissues continues to challenge
current MS technology, largely because of the limits imposed by the complexity of these samples, which contain thousands to tens of
thousands of metabolites. Among the technologies being developed to address this challenge is Nanostructure-Initiator MS (NIMS),[54][55] a
desorption/ ionization approach that does not require the application of matrix and thereby facilitates small-molecule (i.e., metabolite)
identification. MALDI is also used; however, the application of a MALDI matrix can add significant background at <1000 Da that
complicates analysis of the low-mass range (i.e., metabolites). In addition, the size of the resulting matrix crystals limits the spatial resolution
that can be achieved in tissue imaging. Because of these limitations, several other matrix-free desorption/ionization approaches have been
applied to the analysis of biofluids and tissues.

Secondary ion mass spectrometry (SIMS) was one of the first matrix-free desorption/ionization approaches used to analyze metabolites from
biological samples. SIMS uses a high-energy primary ion beam to desorb and generate secondary ions from a surface. The primary
advantage of SIMS is its high spatial resolution (as small as 50 nm), a powerful characteristic for tissue imaging with MS. However, SIMS
has yet to be readily applied to the analysis of biofluids and tissues because of its limited sensitivity at >500 Da and analyte fragmentation
generated by the high-energy primary ion beam. Desorption electrospray ionization (DESI) is a matrix-free technique for analyzing
biological samples that uses a charged solvent spray to desorb ions from a surface. Advantages of DESI are that no special surface is required
and the analysis is performed at ambient pressure with full access to the sample during acquisition. A limitation of DESI is spatial resolution
because "focusing" the charged solvent spray is difficult. However, a recent development termed laser ablation ESI (LAESI) is a promising
approach to circumvent this limitation. Most recently, ion trap techniques such as orbitrap mass spectrometry are also applied to
metabolomics research.[56]

Nuclear magnetic resonance (NMR) spectroscopy is the only detection technique which does not rely on separation of the analytes, and the
sample can thus be recovered for further analyses. All kinds of small molecule metabolites can be measured simultaneously - in this sense,
NMR is close to being a universal detector. The main advantages of NMR are high analytical reproducibility and simplicity of sample
preparation. Practically, however, it is relatively insensitive compared to mass spectrometry-based techniques.[57][58]

Although NMR and MS are the most widely used, modern day techniques other methods of detection that have been used. These include
Fourier-transform ion cyclotron resonance,[59] ion-mobility spectrometry,[60] electrochemical detection (coupled to HPLC), Raman
spectroscopy and radiolabel (when combined with thin-layer chromatography).
 Table 1. Comparison of most common used metabolomics methods
Can be
used in
Compatible
Sensitivity Sample Compatible Compatible Start-up metabolite
Technology with Advantages Disadvantages
(LOD) volume with gases with solids cost imaging
liquids
(MALDI or
DESI)

Quantitative
(with
calibration)
Large body of Destructive
software and (not
databases for recoverable)
metabolite
0.1-0.2 identification Requires
GC-MS 0.5 µM Yes Yes No <$300,000 No sample
mL
Detects most separation
organic and
some Slow (20—
inorganic 40 min per
molecules sample)
Excellent
separation
reproductibility

Destructive
(not
Very flexible recoverable)
technology Not very
10— Detects most quantitative
LC-MS 0.5 nM No Yes Yes >$300,000 Yes
100 µL organic and Slow (15—
some 40 min per
inorganic sample)
molecules Usually
requires
separation

Large
instrument
footprint
Cannot
detect or
identify
Very flexible salts and
technology inorganic
NMR 10— >US$1 Detects most ions
5 µM No Yes Yes Yes
spectroscopy 100 µL million organic and Cannot
some detect non-
inorganic protonated
molecules compounds
Requires
large
sample
volumes
(0.1—0.5
mL)

Statistical methods
The data generated in metabolomics usually consist of measurements performed on subjects under various conditions. These measurements
may be digitized spectra, or a list of metabolite features. In its simplest form, this generates a matrix with rows corresponding to subjects and
columns corresponding with metabolite features (or vice versa).[8] Several statistical programs are currently available for analysis of both
NMR and mass spectrometry data. A great number of free software are already available for the analysis of metabolomics data shown in the
table. Some statistical tools listed in the table were designed for NMR data analyses were also useful for MS data.[61] For mass spectrometry
data, software is available that identifies molecules that vary in subject groups on the basis of mass-over-charge value and sometimes
retention time depending on the experimental design.[62]

Once metabolite data matrix is determined, unsupervised data reduction techniques (e.g. PCA) can be used to elucidate patterns and
connections. In many studies, including those evaluating drug-toxicity and some disease models, the metabolites of interest are not known a
priori. This makes unsupervised methods, those with no prior assumptions of class membership, a popular first choice. The most common of
these methods includes principal component analysis (PCA) which can efficiently reduce the dimensions of a dataset to a few which explain
the greatest variation.[36] When analyzed in the lower-dimensional PCA space, clustering of samples with similar metabolic fingerprints can
be detected. PCA algorithms aim to replace all correlated variables with a much smaller number of uncorrelated variables (referred to as
principal components (PCs)) and retain most of the information in the original dataset.[63] This clustering can elucidate patterns and assist in
the determination of disease biomarkers - metabolites that correlate most with class membership.

Linear models are commonly used for metabolomics data, but are affected by multicollinearity. On the other hand, multivariate statistics are
thriving methods for high-dimensional correlated metabolomics data, of which the most popular one is Projection to Latent Structures (PLS)
regression and its classification version PLS-DA. Other data mining methods, such as random forest, support-vector machines, etc. are
received increasing attention for untargeted metabolomics data analysis.[64] In the case of univariate methods, variables are analyzed one by
one using classical statistics tools (such as Student's t-test, ANOVA or mixed models) and only these with sufficient small p-values are
considered relevant.[35] However, correction strategies should be used to reduce false discoveries when multiple comparisons are conducted
since there is no standard method  for measuring the total amount of metabolites directly in untargeted metabolomics.[65] For multivariate
analysis, models should always be validated to ensure that the results can be generalized.

Machine learning and data mining

Key applications
Toxicity assessment/toxicology by metabolic profiling (especially of urine or blood plasma samples) detects the physiological changes caused
by toxic insult of a chemical (or mixture of chemicals). In many cases, the observed changes can be related to specific syndromes, e.g. a
specific lesion in liver or kidney. This is of particular relevance to pharmaceutical companies wanting to test the toxicity of potential drug
candidates: if a compound can be eliminated before it reaches clinical trials on the grounds of adverse toxicity, it saves the enormous expense
of the trials.[47]

For functional genomics, metabolomics can be an excellent tool for determining the phenotype caused by a genetic manipulation, such as
gene deletion or insertion. Sometimes this can be a sufficient goal in itself—for instance, to detect any phenotypic changes in a genetically
modified plant intended for human or animal consumption. More exciting is the prospect of predicting the function of unknown genes by
comparison with the metabolic perturbations caused by deletion/insertion of known genes. Such advances are most likely to come from
model organisms such as Saccharomyces cerevisiae and Arabidopsis thaliana. The Cravatt laboratory at The Scripps Research Institute has
recently applied this technology to mammalian systems, identifying the N-acyltaurines as previously uncharacterized endogenous substrates
for the enzyme fatty acid amide hydrolase (FAAH) and the monoalkylglycerol ethers (MAGEs) as endogenous substrates for the
uncharacterized hydrolase KIAA1363.[67][68]

Metabologenomics is a novel approach to integrate metabolomics and genomics data by correlating microbial-exported metabolites with
predicted biosynthetic genes.[69] This bioinformatics-based pairing method enables natural product discovery at a larger-scale by refining
non-targeted metabolomic analyses to identify small molecules with related biosynthesis and to focus on those that may not have previously
well known structures.

Fluxomics is a further development of metabolomics. The disadvantage of metabolomics is that it only provides the user with abundances or
concentrations of metabolites, while fluxomics determines the reaction rates of metabolic reactions and can trace metabolites in a biological
system over time.

Nutrigenomics is a generalised term which links genomics, transcriptomics, proteomics and metabolomics to human nutrition. In general, in a
given body fluid, a metabolome is influenced by endogenous factors such as age, sex, body composition and genetics as well as underlying
pathologies. The large bowel microflora are also a very significant potential confounder of metabolic profiles and could be classified as either
an endogenous or exogenous factor. The main exogenous factors are diet and drugs. Diet can then be broken down to nutrients and non-
nutrients. Metabolomics is one means to determine a biological endpoint, or metabolic fingerprint, which reflects the balance of all these
forces on an individual's metabolism.[70][71] Thanks to recent cost reductions, metabolomics has now become accessible for companion
animals, such as pregnant dogs.[72][73]

Plant metabolomics is designed to study the overall changes in metabolites of plant samples and then conduct deep data mining and
chemometric analysis. Specialized metabolites are considered components of plant defense systems biosynthesized in response to biotic and
abiotic stresses.[74]Metabolomics approaches have recently been used to assess the natural variance in metabolite content between individual
plants, an approach with great potential for the improvement of the compositional quality of crops.[75]

See also
Biology portal

Technology portal

Medicine portal
 Epigenomics
Fluxomics
Genomics
Lipidomics
Molecular epidemiology
Molecular medicine
Molecular pathology
Precision medicine
Proteomics
Transcriptomics
XCMS Online, a bioinformatics software designed for statistical analysis of mass spectrometry data

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Further reading
Bundy JG, Davey MP, Viant MR (2009). "Environmental metabolomics: A critical review and future perspectives".
Metabolomics. 5: 3–21. doi:10.1007/s11306-008-0152-0 (https://doi.org/10.1007%2Fs11306-008-0152-0).
S2CID 22179989 (https://api.semanticscholar.org/CorpusID:22179989).
 Claudino WM, Quattrone A, Biganzoli L, Pestrin M, Bertini I, Di Leo A (July 2007). "Metabolomics: available results, current
research projects in breast cancer, and future applications" (https://web.archive.org/web/20080120072634/http://lab.bcb.ia
state.edu/projects/plantmetabolomics/). Journal of Clinical Oncology. 25 (19): 2840–2846. doi:10.1200/JCO.2006.09.7550
(https://doi.org/10.1200%2FJCO.2006.09.7550). PMID 17502626 (https://pubmed.ncbi.nlm.nih.gov/17502626). Archived
from the original (http://lab.bcb.iastate.edu/projects/plantmetabolomics/) on 2008-01-20.
Ellis DI, Dunn WB, Griffin JL, Allwood JW, Goodacre R (September 2007). "Metabolic fingerprinting as a diagnostic tool".
Pharmacogenomics. 8 (9): 1243–1266. doi:10.2217/14622416.8.9.1243 (https://doi.org/10.2217%2F14622416.8.9.1243).
PMID 17924839 (https://pubmed.ncbi.nlm.nih.gov/17924839).
Ellis DI, Goodacre R (August 2006). "Metabolic fingerprinting in disease diagnosis: biomedical applications of infrared and
Raman spectroscopy". The Analyst. 131 (8): 875–885. Bibcode:2006Ana...131..875E (https://ui.adsabs.harvard.edu/abs/2
006Ana...131..875E). doi:10.1039/b602376m (https://doi.org/10.1039%2Fb602376m). PMID 17028718 (https://pubmed.nc
bi.nlm.nih.gov/17028718).
Fan TW, Lorkiewicz PK, Sellers K, Moseley HN, Higashi RM, Lane AN (March 2012). "Stable isotope-resolved
metabolomics and applications for drug development" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3471671).
Pharmacology & Therapeutics. 133 (3): 366–391. doi:10.1016/j.pharmthera.2011.12.007 (https://doi.org/10.1016%2Fj.phar
mthera.2011.12.007). PMC 3471671 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3471671). PMID 22212615 (https://pu
bmed.ncbi.nlm.nih.gov/22212615).
Haug K, Salek RM, Conesa P, Hastings J, de Matos P, Rijnbeek M, et al. (January 2013). "MetaboLights--an open-access
general-purpose repository for metabolomics studies and associated meta-data" (https://www.ncbi.nlm.nih.gov/pmc/article
s/PMC3531110). Nucleic Acids Research. 41 (Database issue): D781–D786. doi:10.1093/nar/gks1004 (https://doi.org/10.
1093%2Fnar%2Fgks1004). PMC 3531110 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3531110). PMID 23109552 (htt
ps://pubmed.ncbi.nlm.nih.gov/23109552).
Tomita M, Nishioka T (2005). Metabolomics: The Frontier of Systems Biology. Springer. ISBN 4-431-25121-9.
Weckwerth W (2006). Metabolomics: Methods And Protocols (Methods in Molecular Biology) (https://archive.org/details/me
tabolomicsmeth00weck_0). Humana Press. ISBN 1-588-29561-3. OCLC 493824826 (https://www.worldcat.org/oclc/49382
4826).

External links
Metabolism (https://curlie.org/Science/Biology/Biochemistry_and_Molecular_Biology/Metabolism) at Curlie
Human Metabolome Database (HMDB) (http://www.hmdb.ca/)
METLIN (http://metlin.scripps.edu/)
XCMS (https://web.archive.org/web/20101228002337/http://metlin.scripps.edu/xcms/)
LCMStats (https://sourceforge.net/projects/lcmstats/)
Metabolights (http://www.ebi.ac.uk/metabolights/)
NIH Common Fund Metabolomics Consortium (http://metabolomics.info)
Metabolomics Workbench (http://metabolomicsworkbench.org)
Golm Metabolome Database (http://gmd.mpimp-golm.mpg.de/)
Metabolon (https://www.metabolon.com/)

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