A guide to metabolic flux analysis in metabolic engineering: Methods,tools and applications |
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| Institution: | 1. Vesalius Research Center, VIB, Leuven, Belgium;2. Department of Oncology, KU Leuven, Leuven, Belgium;3. Department of Chemical and Biomolecular Engineering, University of Delaware, Newark, DE, USA;4. Department of Pediatrics, UCLA School of Medicine, Los Angeles Biomedical Research Institute at the Harbor-UCLA Medical Center and Sidmap, LLC, Los Angeles, CA, USA;5. Advanced Imaging Research Center-Division of Metabolic Mechanisms of Disease and Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, TX, USA;6. Department of Nutrition, Case Western Reserve University School of Medicine, Cleveland, OH, USA;7. Broad Institute of Harvard and MIT, Cambridge, MA, USA;8. Children''s Medical Center Research Institute, UT Southwestern Medical Center, Dallas, TX, USA;9. Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, Brussels, Belgium;10. MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus, Cambridge, UK;11. Cancer Research UK, Beatson Institute, Glasgow, UK;12. Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-Belval, Luxembourg;13. Goodman Cancer Research Centre, Department of Physiology, McGill University, Montreal, QC, Canada;14. Institute of Cancer Sciences, University of Glasgow, Glasgow, UK;15. Internal Medicine, Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA;16. Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA;17. Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA;18. Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, USA;19. Advanced Imaging Research Center-Division of Metabolic Mechanisms of Disease and Department of Radiology, The University of Texas Southwestern Medical Center, Dallas, TX, USA;20. Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA;21. L’Institut des Technologies Avancées en Sciences du Vivant (ITAV), Toulouse Cedex 1, France;22. The University of Arizona Cancer Center, and Department of Nutritional Sciences, The University of Arizona, Tucson, AZ, USA;23. Department of Biochemistry, University of Rochester Medical Center, Rochester, NY, USA;24. Department of Biophysics, University of Rochester Medical Center, Rochester, NY, USA;25. Institute of Bio- and Geosciences, IBG-1: Biotechnology, Forschungszentrum Jülich GmbH, Jülich, Germany;26. Department of Chemistry and Lewis–Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA;27. Cambridge Systems Biology Centre and Department of Biochemistry, University of Cambridge, Cambridge, UK;28. Division of Physiology and Metabolism, MRC National Institute for Medical Research, London, UK;29. Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland;30. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA;31. Goodman Cancer Research Centre, and Department of Biochemistry, McGill University, Montreal, Quebec, Canada;32. School of Cancer Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK;33. Institute of Systems Biotechnology, Saarland University, Saarbrücken, Germany;34. Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology, Broad Institute of Harvard and MIT, Cambridge, MA, USA;35. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA;36. Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, USA;37. Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA;1. Department of Chemical and Biomolecular Engineering, University of Delaware, Newark, DE, USA;2. Ammon-Pinizzotto Biopharmaceutical Innovation Center, University of Delaware, Newark, DE, USA;3. Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA |
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| Abstract: | The field of metabolic engineering is primarily concerned with improving the biological production of value-added chemicals, fuels and pharmaceuticals through the design, construction and optimization of metabolic pathways, redirection of intracellular fluxes, and refinement of cellular properties relevant for industrial bioprocess implementation. Metabolic network models and metabolic fluxes are central concepts in metabolic engineering, as was emphasized in the first paper published in this journal, “Metabolic fluxes and metabolic engineering” (Metabolic Engineering, 1: 1–11, 1999). In the past two decades, a wide range of computational, analytical and experimental approaches have been developed to interrogate the capabilities of biological systems through analysis of metabolic network models using techniques such as flux balance analysis (FBA), and quantify metabolic fluxes using constrained-based modeling approaches such as metabolic flux analysis (MFA) and more advanced experimental techniques based on the use of stable-isotope tracers, i.e. 13C-metabolic flux analysis (13C-MFA). In this review, we describe the basic principles of metabolic flux analysis, discuss current best practices in flux quantification, highlight potential pitfalls and alternative approaches in the application of these tools, and give a broad overview of pragmatic applications of flux analysis in metabolic engineering practice. |
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| Keywords: | Metabolic flux analysis Flux balance analysis Metabolism Metabolic network model Stable-isotope tracers Systems biology |
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