NationMaster - Encyclopedia: Metabolomics

Metabolomics is the "systematic study of the unique chemical fingerprints that specific cellular processes leave behind" - specifically, the study of their small-molecule metabolite profiles.^[1] The metabolome represents the collection of all metabolites in a biological organism, which are the end products of its gene expression. Thus, while mRNA gene expression data and proteomic analyses do not tell the whole story of what might be happening in a cell, metabolic profiling can give an instantaneous snapshot of the physiology of that cell. One of the challenges of systems biology is to integrate proteomic, transcriptomic, and metabolomic information to give a more complete picture of living organisms. Gene expression, or simply expression, is the process by which a genes DNA sequence is converted into the structures and functions of a cell. ... ECAN Genesis 2000 robot preparing Ciphergen SELDI-TOF protein chips for proteomic pattern analysis. ... Systems biology is the study of the interactions between the components of a biological system, and how these interactions give rise to the function and behaviour of that system (for example, the enzymes and metabolites in a metabolic pathway)[1][2]. Typically, a cellular network is modelled mathematically. ... ECAN Genesis 2000 robot preparing Ciphergen SELDI-TOF protein chips for proteomic pattern analysis. ... The Transcriptome is the set of all mRNA molecules (or transcripts) in one or a population of biological cells for a given set of environmental circumstances. ...

1 Metabolome
2 Metabolites
3 Metabonomics
4 History
5 Analytical technologies: separation methods
6 Analytical technologies: detection methods
7 Key applications
8 See also
9 Sources and notes
10 Further reading

Metabolome

Metabolome refers to the complete set of small-molecule metabolites (such as metabolic intermediates, hormones and other signalling molecules, and secondary metabolites) to be found within a biological sample, such as a single organism.^[2] 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. In January 2007 scientists at the University of Alberta and the University of Calgary completed the first draft of the human metabolome. They have catalogued and characterized 2,500 metabolites, 1,200 drugs and 3,500 food components that can be found in the human body.^[3] The Transcriptome is the set of all mRNA molecules (or transcripts) in one or a population of biological cells for a given set of environmental circumstances. ... ECAN Genesis 2000 robot preparing Ciphergen SELDI-TOF protein chips for proteomic pattern analysis. ... Oral medication Caffeine is the most widely used psychoactive substance in the world. ...

Metabolites

Metabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. 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. Overview of the citric acid cycle The citric acid cycle, one of the central metabolic pathways in aerobic organisms. ... In chemistry, a molecule is an aggregate of two or more atoms in a definite arrangement held together by chemical bonds [1] [2] [3] [4] [5]. Chemical substances are not infinitely divisible into smaller fractions of the same substance: a molecule is generally considered the smallest particle of a pure... Secondary metabolites are those chemical compounds in organisms that are not directly involved in the normal growth, development or reproduction of organisms. ... Ernst Haeckel coined the term oekologie in 1866. ... An antibiotic is a drug that kills or slows the growth of bacteria. ... For animal and plant pigments, see Pigment, biology. ...

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. Metabolome is the whole set of metabolic entities and small pathway motifs in a cell, tissue, organ, organisms, and species. ... Santorio Santorio (1561-1636) in his steelyard balance, from Ars de statica medecina, first published 1614 Metabolism (from μεταβολισμος(metavallo), the Greek word for change), in the most general sense, is the ingestion and breakdown of complex compounds, coupled... Neuraminidase ribbon diagram An enzyme (in Greek en = in and zyme = blend) is a protein, or protein complex, that catalyzes a chemical reaction and also controls the 3D orientation of the catalyzed substrates. ... A chemical reaction occurs when vapours of hydrogen chloride in a beaker and ammonia in a test tube meet to form a cloud of a new substance, ammonium chloride A chemical reaction is a process that results in the interconversion of chemical substances [1]. The substance or substances initially involved... The quasispecies [kwaa-zei-spee-seez] model is a description of the process of the Darwinian evolution of self-replicating entities within the framework of physical chemistry. ...

Metabonomics

Metabonomics is defined as "the quantitative measurement of the dynamic multiparametric metabolic response of living systems to pathophysiological stimuli or genetic modification". This approach originated in Imperial College London and has been used in toxicology, disease diagnosis and a number of other fields.^[4]

There is some disagreement over the exact differences between 'metabolomics' and 'metabonomics'; in general, the term 'metabolomics' is more commonly used. 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 the difference resides in the fact that 'metabolomics' places a greater emphasis on comprehensive metabolic profiling, while 'metabonomics' is used to describe multiple (but not necessarily comprehensive) metabolic changes caused by a biological perturbation. In practice, there is still a large degree of overlap in the way the terms are used, and they are often in effect synonymous.

History

Metabolic biochemists have arguably been 'doing metabolomics' for decades. The chromatographic separation techniques that made the initial detection of metabolites possible were developed in the late 1960's, which marks the technical origin of the field. ^[5]

Metabolomics began develop in 1970 by Arthur Robinson investigating Pauling's ideas as to whether biological variability could be explained on the basis of far wider ranges of nutritional requirements than what was generally recognized. In analyzing the "messy" chromatographic patterns of urine from vitamin B6-loaded subjects, Robinson realized that the patterns of hundreds or thousands of chemical constituents in urine contained much useful information.

Although it was not called metabolomics, the first paper devoted to this topic was titled, “Quantitative Analysis of Urine Vapor and Breath by Gas-Liquid Partition Chromatography”, by Robinson and Pauling in 1971 and published in the Proceedings of the National Academy of Sciences. Since then, Robinson has had nineteen more papers published on the quantitative patterns of metabolites in body fluids (see below). Robinson and colleagues have identified several diseases, conditions, and physiological age based on this data. It was his expectation that body fluid analysis can be optimized to make a low cost, information-rich, medically-relevant means of measuring metabolically-driven changes in functional state, even when the chemical constituents are all in the “normal range”.

The core idea that Robinson conceived is that information-rich data that reflects the functional status of a complex biological system resides in the quantitative and qualitative pattern of metabolites in body fluids. Twenty years later, others began to realize the value of this approach, and interest in this has mushroomed. The name metabolomics was coined in the 1990s (the first paper using the word metabolome is Oliver, S. G., Winson, M. K., Kell, D. B. & Baganz, F. (1998). Systematic functional analysis of the yeast genome. Trends Biotechnol. 16, 373-378), and in 2004 a society was formed to promote its study. Many of the bioanalytical methods used for metabolomics have been adapted (or in some cases simply adopted) from existing biochemical techniques. Two characteristics common to metabolomic research are:

Metabolites are profiled without bias towards a specific metabolite or group of metabolites
Relationships between the metabolites are characterized, currently mostly by multivariate methods.

On January 23rd 2007 the Human Metabolome Project, led by Dr. David Wishart of the University of Alberta, Canada, completed the first draft of the human metabolome, consisting of 2,500 metabolites, 1,200 drugs and 3,500 food components.

Analytical technologies: separation methods

There are two issues to be addressed for metabolite analysis: 1. separation of the analytes, usually by chromatography. Electrophoresis, particularly capillary electrophoresis, is also used. 2. Detection of the analytes, following separation by chromatographic or other methods. A chemist is shown using column chromatographic apparatus in the mid-1950s to separate constituents in a coal tar color analysis Pictured is a sophisticated gas chromatography system. ...

Gas chromatography, especially when interfaced with mass spectrometry (GC-MS), is one of the most widely used and powerful methods. It offers very high chromatographic resolution, but requires chemical derivatization for many biomolecules: only volatile chemicals can be analysed without derivatization. (Some modern instruments allow '2D' chromatography, using a short polar column after the main analytical column, which increases the resolution still further.) Some large and polar metabolites cannot be analysed by GC.

High performance liquid chromatography (HPLC). Compared to GC, HPLC has lower chromatographic resolution, but it does have the advantage that a much wider range of analytes can potentially be measured.

Capillary electrophoresis (CE). So far, there are only a relatively small number of publications on use of CE for metabolite profiling. This will no doubt change, as there are a number of advantages of CE: it has a higher theoretical separation efficiency than HPLC, 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.

Gas-liquid chromatography (GLC), or simply gas chromatography (GC) is a type of chromatography in which the mobile phase is a carrier gas, usually an inert gas such as helium or nitrogen, and the stationary phase is a microscopic layer of liquid on an inert solid support. ... Capillary electrophoresis (CE) can be used to separate ionic species by their charge and frictional forces. ...

Analytical technologies: detection methods

Mass spectrometry (MS) is used to identify and to quantify metabolites after separation by GC, HPLC, or CE. GC-MS is the most 'natural' combination of the three, and was the first to be developed. In addition, mass spectral fingerprint libraries exist or can be developed that allow identification of a metabolite according to its fragmentation pattern. MS is both sensitive (although, particularly for HPLC-MS, sensitivity is more of an issue as it is affected by the charge on the metabolite, and can be subject to ion suppression artifacts) and can be very specific. There are also a number of studies which use MS as a stand-alone technology: the sample is infused directly into the mass spectrometer with no prior separation, and the MS serves to both separate and to detect metabolites.

Nuclear magnetic resonance (NMR) spectroscopy. NMR 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 metabolite can be measured simultaneously - NMR is close to being a universal detector. However, it also possesses one major disadvantage, which is that it is relatively insensitive compared to mass spectrometry-based techniques.

Other techniques. MS and NMR are by far the two leading technologies for metabolomics. Other methods of detection that have been used include electrochemical detection (coupled to HPLC) and radiolabel (when combined with thin-layer chromatography).

Basic schematic of a mass spectrometer Mass spectrometry (also known as mass spectroscopy (deprecated)[1] or in common speech mass-spec) is an analytical technique used to measure the mass-to-charge ratio of ions. ... Pacific Northwest National Laboratorys high magnetic field (800 MHz, 18. ...

Key applications

Toxicity assessment/toxicology. Metabolic profiling (especially of urine or blood plasma samples) can be used to detect 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.

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.

Nutrigenomics is a generalised term which links genomics, transcriptomics, proteomics and metabolomics to human nutrition. In general a metabolome in a given body fluid 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.^[6]

// Toxic and Intoxicated redirect here â€“ toxic has other uses, which can be found at Toxicity (disambiguation); for the state of being intoxicated by alcohol see Drunkenness. ... Toxicology (from the Greek words toxicos and logos [1]) is the study of the adverse effects of chemicals on living organisms [2]. It is the study of symptoms, mechanisms, treatments and detection of poisoning, especially the poisoning of people. ... Oral medication A medication is a licenced drug taken to cure or reduce symptoms of an illness or medical condition. ... In medicine, a clinical trial (synonyms: clinical studies, research protocols, medical research) is a type of research study. ... Functional genomics is a field of molecular biology that is attempting to make use of the vast wealth of data produced by genome sequencing projects to describe genome function. ... Individuals in the mollusk species Donax variabilis show diverse coloration and patterning in their phenotypes. ... For other meanings of this term, see gene (disambiguation). ... A model organism is a species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the organism model will provide insight into the workings of other organisms. ... Binomial name Saccharomyces cerevisiae Meyen ex E.C. Hansen PPOOOOOOP is a species of budding yeast. ... Binomial name Arabidopsis thaliana (L.) Heynh. ... Nutrigenomics is the application of the sciences of genomics, transcriptomics, proteomics and metabolomics to human nutrition, especially the relationship between nutrition and health. ...

Sources and notes

^ B. Daviss, "Growing pains for metabolomics," The Scientist, 19[8]:25-28, April 25, 2005
^ First use of the term "metabolome" in the literature — Oliver, S. G., Winson, M. K., Kell, D. B. & Baganz, F. (1998). "Systematic functional analysis of the yeast genome". Trends Biotechnol. 16 (10): 373–378. PMID 9744112.
^
- First book on metabolomics — Harrigan, G. G. & Goodacre, R. (eds) (2003). RMetabolic Profiling: Its Role in Biomarker Discovery and Gene Function Analysis. Kluwer Academic Publishers (Boston). ISBN xxx-xxx.
- Fiehn, O., Kloska, S. & Altmann, T. (2001). "Integrated studies on plant biology using multiparallel techniques". Curr. Opin. Biotechnol. 12 (1): 82–86. PMID 11167078..
- Fiehn, O. (2001). "Combining genomics, metabolome analysis, and biochemical modelling to understand metabolic networks.". Comp. Funct. Genomics 2 (3): 155–168. Publisher abstract link
- Weckwerth, W. Metabolomics in systems biology. Annu. Rev. Plant Biol. 54, 669–689 (2003).
- Goodacre, R., Vaidyanathan, S., Dunn, W. B., Harrigan, G. G. & Kell, D. B. Metabolomics by numbers: acquiring and understanding global metabolite data. Trends Biotechnol. 22, 245–252 (2004).
- Nicholson, J. K., Holmes, E., Lindon, J. C. & Wilson, I. D. The challenges of modeling mammalian biocomplexity. Nature Biotechnol. 22, 1268–1274 (2004). Stresses the role of intestinal microorganisms in contributing to the human metabolome.
- van der Greef, J., Stroobant, P. & van der Heijden, R. The role of analytical sciences in medical systems biology. Curr. Opin. Chem. Biol. 8, 559–565 (2004).
- Kell, D. B. Metabolomics and systems biology: making sense of the soup. Curr. Opin. Microbiol. 7, 296–307 (2004).
- Dunn, W.B. and Ellis, D.I. (2005) Metabolomics: current analytical platforms and methodologies. Trends in Analytical Chemistry 24(4), 285-294.
- Ellis, D.I. and Goodacre, R. (2006) Metabolic fingerprinting in disease diagnosis: biomedical applications of infrared and Raman spectroscopy, Analyst, 131, 875-885. DOI:10.1039/b602376m
^
- Nicholson, J. K., Lindon, J. C., Holmes, E. (1999). “Metabonomics”: understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data. Xenobiotica. 11: p.1181-1189.
- Lindon, J.C., Holmes, E., Bollard, M.E., Stanley, E.G., and Nicholson, J.K. (2004) Metabonomics technologies and their applications in physiological monitoring, drug safety assessment and disease diagnosis. Biomarkers. Vol. 9, No. 1. p.1-/31.
- Brindle, J.T., , Antti, H., Holmes, E., Tranter, G., Nicholson, J.K., Bethell, H.W.L., Clarke, S., Schofield, P.M., McKilligan, E., Mosedale, D.E., & Grainger, D.J. (2002) Rapid and non-invasive diagnosis of the presence and severity of coronary heart disease using 1H NMR -based metabonomics. Nature Medicine. 8 (12): p.1439-1444.
- Bollard, M.E., Stanley, E.G., Lindon, J.C., Nicholson, J.K., & Holmes, E. (2005) NMR-based metabonomic approaches for evaluating physiological influences on biofluid composition. NMR Biomed. 2005: p.18:143–162.
^ Preti, George. "Metabolomics comes of age?" The Scientist, 19[11]:8, June 6, 2005.
^ The European Nutrigenomics Network

Pauling, L.C., Robinson, A.B., Teranishi, R., and Cary, P., Quantitative Analysis of Urine Vapor and Breath by Gas-Liquid Partition Chromatography, Proc. Natl. Acad. Sci. (1971) 68, 2374-2376.
Teranishi, R. and Mon, T.R. and Robinson, A.B., Cary, P., and Pauling, L.C., Gas Chromatography of Volatiles from Breath and Urine, Analytical Chemistry 44 (1972) pp 18-20.
Robinson, A.B. and Pauling, L.C., Quantitative Chromatographic Analysis in Orthomolecular Medicine, Orthomolecular Psychiatry, 1973, ed. D. Hawkins, pp 35-53.
Robinson, A.B., Partridge, D., Turner, M., Teranishi, R., and Pauling, L.C., An Apparatus for the Quantitative Analysis of Volatile Compounds in Urine, J. Chromatography (1973) 85, pp 19-29.
Matsumoto, K.E., Partridge, D.H., Robinson, A.B., and Pauling, L.C. and Flath, R. A., Mon, T.R., and Teranishi, R., The Identification of Volatile Compounds in Human Urine, J. Chromatography 85 (1973) pp 31-34.
Pauling, L.C. and Robinson, A.B., Techniques of Orthomolecular Medicine, First Conference on the Analysis of Multicomponent Mixtures and their Application to Health-Related Problems (1973) 1, pp 1-7.
Robinson, A.B., Cary, P., Dore, B., Keaveny, I., Brenneman, L., Turner, M. and Pauling, L., Orthomolecular Diagnosis of Mental Retardation and Diurnal Variation in Normal Subjects by Low-Resolution Gas-Liquid Chromatography of Urine, Int. Research Comm. Sys. (1973) 70, p 3.
Robinson, A.B. and Westall, F.C., The Use of Urinary Amine Measurement for Orthomolecular Diagnosis of Multiple Sclerosis, J. Orth. Psych. (1974) 3, pp 1-10.
Robinson, A.B., Westall, F.C., and Ellison, G.W., Multiple Sclerosis: Urinary Amine Measurement for Orthomolecular Diagnosis, Life Sciences (1974) 14 pp 1747-1753.
Robinson, A.B. and Pauling, L.C., Techniques of Orthomolecular Diagnosis, Clinical Chemistry (1974) 20 pp 961-965.
Robinson, A.B., Orthomolecular Medicine – Diagnosis and Therapy, Proc. 8th Annual Conference National Society For Autistic Children (1974) pp 1-8.
Robinson, A.B., Looking for Optimum Health: A Guided Tour Through the Linus Pauling Institute (1975) Prevention, pp 89-96.
Robinson, A.B., Weiss, M., Reynolds, W.E., and Robinson, L.R., Use of Mass Spectrometry for Orthomolecular Diagnosis (1975) Proceedings Twenty-Third Annual Conference on Mass Spectrometry and Allied Topics, pp 182-184.
Rosenberg, R.N., Robinson, A.B., and Partridge, D., Urine Vapor Pattern for Olivopontocerebellar Degeneration (1975) Clinical Biochemistry 8, pp 365-368.
Dirren, H., Robinson, A.B., and Pauling, L.C., Sex-Related Patterns in the profiles of Human Urinary Amino Acids, Clinical Chemistry (1975) 21, pp 1970-1975.
Robinson, A.B., Willioughby, R., and Robinson, L.R., Age Dependent Amines, Amides, and Amino Acid Residues in Drosophila Melanogaster, Experimental Gerontology (1976) 11, pp 113-120.
Robinson, A.B., Dirren, H., and Sheets, A. and Miquel, J. and Lundgren, P.R., Quantitative Aging Pattern in Mouse Urine Vapor as Measured by Gas-Liquid Chromatography, Experimental Gerontology (1976) 11, pp 11-16.
Robinson, A.B., Pauling, L.C., and Aberth, W., A Controversy: Diagnosis of Infectious Hepatitis (1977) Clinical Chemistry 23, pp 908-910.
Robinson, A.B., Molecular Clocks, Molecular Profiles, and Optimum Diets: Three Approaches to the Problem of Aging (1979) Mechanisms of Ageing and Development 9, pp 225-236.
Robinson, A.B. and Robinson, L.R., Quantitative Measurement of Human Physiological Age by Profiling of Body Fluids and Pattern Recognition (1991) Mechanisms of Ageing and Development 59, pp 47-67.
Tomita M., Nishioka T. (2005), Metabolomics: The Frontier of Systems Biology, Springer, ISBN 4-431-25121-9
Wolfram Weckwerth W. (2006), Metabolomics: Methods And Protocols (Methods in Molecular Biology), Humana Press, ISBN 1-58829-561-3
Dunn, W.B. and Ellis, D.I. (2005), Metabolomics: current analytical platforms and methodologies. Trends in Analytical Chemistry 24(4), 285-294.
Ellis, D.I. and Goodacre, R. (2006) Metabolic fingerprinting in disease diagnosis: biomedical applications of infrared and Raman spectroscopy. Analyst 131, 875-885. DOI:10.1039/b602376m

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