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Metabolomics and systems pharmacology: why and how to model the human metabolic network for drug discovery☆

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      Highlights

      • We now have metabolic network models; the metabolome is represented by their nodes.
      • Metabolite levels are sensitive to changes in enzyme activities.
      • Drugs hitchhike on metabolite transporters to get into and out of cells.
      • The consensus network Recon2 represents the present state of the art, and has predictive power.
      • Constraint-based modelling relates network structure to metabolic fluxes.

      Abstract

      Metabolism represents the ‘sharp end’ of systems biology, because changes in metabolite concentrations are necessarily amplified relative to changes in the transcriptome, proteome and enzyme activities, which can be modulated by drugs. To understand such behaviour, we therefore need (and increasingly have) reliable consensus (community) models of the human metabolic network that include the important transporters. Small molecule ‘drug’ transporters are in fact metabolite transporters, because drugs bear structural similarities to metabolites known from the network reconstructions and from measurements of the metabolome. Recon2 represents the present state-of-the-art human metabolic network reconstruction; it can predict inter alia: (i) the effects of inborn errors of metabolism; (ii) which metabolites are exometabolites, and (iii) how metabolism varies between tissues and cellular compartments. However, even these qualitative network models are not yet complete. As our understanding improves so do we recognise more clearly the need for a systems (poly)pharmacology.

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      Most cited references 464

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      Cytoscape 2.8: new features for data integration and network visualization

      Summary: Cytoscape is a popular bioinformatics package for biological network visualization and data integration. Version 2.8 introduces two powerful new features—Custom Node Graphics and Attribute Equations—which can be used jointly to greatly enhance Cytoscape's data integration and visualization capabilities. Custom Node Graphics allow an image to be projected onto a node, including images generated dynamically or at remote locations. Attribute Equations provide Cytoscape with spreadsheet-like functionality in which the value of an attribute is computed dynamically as a function of other attributes and network properties. Availability and implementation: Cytoscape is a desktop Java application released under the Library Gnu Public License (LGPL). Binary install bundles and source code for Cytoscape 2.8 are available for download from http://cytoscape.org. Contact: msmoot@ucsd.edu
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        Network medicine: a network-based approach to human disease.

        Given the functional interdependencies between the molecular components in a human cell, a disease is rarely a consequence of an abnormality in a single gene, but reflects the perturbations of the complex intracellular and intercellular network that links tissue and organ systems. The emerging tools of network medicine offer a platform to explore systematically not only the molecular complexity of a particular disease, leading to the identification of disease modules and pathways, but also the molecular relationships among apparently distinct (patho)phenotypes. Advances in this direction are essential for identifying new disease genes, for uncovering the biological significance of disease-associated mutations identified by genome-wide association studies and full-genome sequencing, and for identifying drug targets and biomarkers for complex diseases.
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          Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease

          Metabolomics studies hold promise for discovery of pathways linked to disease processes. Cardiovascular disease (CVD) represents the leading cause of death and morbidity worldwide. A metabolomics approach was used to generate unbiased small molecule metabolic profiles in plasma that predict risk for CVD. Three metabolites of the dietary lipid phosphatidylcholine, namely choline, trimethylamine N-oxide (TMAO), and betaine, were identified and then shown to predict risk for CVD in an independent large clinical cohort. Dietary supplementation of mice with choline, TMAO or betaine promoted up-regulation of multiple macrophage scavenger receptors linked to atherosclerosis, and supplementation with choline or TMAO promoted atherosclerosis. Studies using germ-free mice confirmed a critical role for dietary choline and gut flora in TMAO production, augmented macrophage cholesterol accumulation and foam cell formation. Suppression of intestinal microflora in atherosclerosis-prone mice inhibited dietary choline-enhanced atherosclerosis. Genetic variations controlling expression of flavin monooxygenases (FMOs), an enzymatic source of TMAO, segregated with atherosclerosis in hyperlipidemic mice. Discovery of a relationship between gut flora-dependent metabolism of dietary phosphatidylcholine and CVD pathogenesis provides opportunities for development of both novel diagnostic tests and therapeutic approaches for atherosclerotic heart disease.
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            Author and article information

            Affiliations
            School of Chemistry and Manchester Institute of Biotechnology, The University of Manchester, 131 Princess Street, Manchester M1 7DN, UK
            Author notes
            [* ] Corresponding author. dbk@ 123456manchester.ac.uk
            Contributors
            Journal
            Drug Discov Today
            Drug Discov. Today
            Drug Discovery Today
            Elsevier Science Ltd., Distributed by Virgin Mailing and Distribution
            1359-6446
            1878-5832
            1 February 2014
            February 2014
            : 19
            : 2
            : 171-182
            23892182 3989035 S1359-6446(13)00248-1 10.1016/j.drudis.2013.07.014
            © 2014 The Authors

            This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/).

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            Pharmacology & Pharmaceutical medicine

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