Abstract
Cellular complexity makes it difficult to build a complete understanding of cellular function but also offers innumerable possibilities for modifying the cellular machinery to achieve a specific purpose. The exploitation of cellular complexity for strain improvement has been a challenging goal for applied biological research because it requires the coordinated understanding of multiple cellular processes. It is therefore pursued most efficiently in the framework of systems biology. Progress in strain improvement will depend not only on advances in technologies for high-throughput measurements but, more importantly, on the development of theoretical methods that increase the information content of these measurements and, as such, facilitate the elucidation of mechanisms and the identification of genetic targets for modification.
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References
Hemmi, H. et al. Identification of genes affecting lycopene formation in Escherichia coli transformed with carotenoid biosynthetic genes: candidates for early genes in isoprenoid biosynthesis. J. Biochem. 123, 1088–1096 (1998).
Badarinarayana, V. et al. Selection analyses of insertional mutants using subgenic-resolution arrays. Nat. Biotechnol. 19, 1060–1065 (2001).
Ideker, T. & Lauffenburger, D. Building with a scaffold: emerging strategies for high to low-level cellular modeling. Trends Biotechnol. 21, 255–262 (2003).
Edwards, J.S. & Palsson, B. The Escherichia coli MG1655 in silico metabolic genotype: Its definition, characteristics, and capabilities. Proc. Natl. Acad. Sci. USA 97, 5528–5533 (2000).
Segre, D., Vitkup, D. & Church, G.M. Analysis of optimality in natural and perturbed metabolic networks. Proc. Natl. Acad. Sci. USA 99, 15112–15117 (2002).
Stephanopoulos, G., Aristidou, A. & Nielsen, J. Metabolic Engineering: Principles and Methodologies (Academic Press, San Diego, 1998).
Stephanopoulos, G. & Vallino, J.J. Network rigidity and metabolic engineering in metabolite overproduction. Science 252, 1675–1681 (1991).
Kacser, H. & Burns, J.A. The control of flux. Symp. Soc. Exp. Biol. 27, 65–104 (1973).
Koffas, M.A., Jung, G.Y. & Stephanopoulos, G. Engineering metabolism and product formation in Corynebacterium glutamicum by coordinated gene overexpression. Metab. Eng. 5, 32–41 (2003).
Stephanopoulos, G. Metabolic Fluxes and Metabolic Engineering. Metab. Eng. 1, 1–10 (1999).
Colon, G.E., Nguyen, T.T., Jetten, M.S., Sinskey, A.J. & Stephanopoulos, G. Production of isoleucine by overexpression of ilvA in a Corynebacterium lactofermentum threonine producer. Appl. Microbiol. Biotechnol. 43, 482–488 (1995).
Cremer, J. et al. Control of the lysine biosynthesis sequence in corynebacterium glutamicum as analyzed by overexpression of the individual corresponding genes. Appl. Environ. Microbiol. 57, 1746–1752 (1991).
Koffas, M.A., Jung, G.Y., Aon, J.C. & Stephanopoulos, G. Effect of pyruvate carboxylase overexpression on the physiology of Corynebacterium glutamicum. Appl. Environ. Microbiol. 68, 5422–5428 (2002).
Berrios-Rivera, S.J., Bennett, G.N. & San, K.-Y. The effect of increasing NADH availability on the redistribution of metabolic fluxes in Escherichia coli chemostat cultures. Metab. Eng. 4, 230–237 (2002).
Cameron, D.C. et al. Metabolic engineering of propanediol pathways. Biotechnol. Prog. 14, 116–125 (1998).
Causey, T.B., Shanmugam, K.T., Yomano, L.P. & Ingram, L.O. Engineering Escherichia coli for efficient conversion of glucose to pyruvate. Proc. Natl. Acad. Sci. USA 101, 2235–2240 (2003).
Farmer, W.R. & Liao, J.C. Improving lycopene production in Escherichia coli by engineering metabolic control. Nat. Biotechnol. 18, 533–537 (2000).
Fussenegger, M. & Betenbaugh, M.J. Metabolic engineering II. Eukaryotic systems. Biotechnol. Bioeng. 79, 509–531 (2002).
Kaup, B. et al. Metabolic engineering of Escherichia coli: construction of an efficient biocatalyst for d-mannitol formation in a whole-cell biotransformation. Appl. Microbiol. Biotechnol. 64, 333–339 (2004).
Khosla, C. & Bailey, J.E. Heterologous expression of a bacterial hemoglobin improves the growth properties of recombinant Escherichia coli. Nature 331, 633–635 (1988).
Lee, S.Y. & Lee, Y. Metabolic engineering of Escherichia coli for production of enantiomerically pure (R)-(-)-hydroxycarboxylic acids. Appl. Environ. Microbiol. 69, 3421–3426 (2003).
Martin, V.J.J. et al. Engineering the mevalonate pathway in Escherichia coli for production of terpenoids. Nat. Biotechnol. 21, 796–802 (2003).
Nakamura, C. & Whited, G. Metabolic engineering for the microbial production of 1,3-propanediol. Curr. Opin. Biotechnol. 14, 454–459 (2003).
Ostergaard, S. et al. Increasing galactose consumption by Saccharomyces cerevisiae through metabolic engineering of the GAL gene regulatory network. Nat. Biotechnol. 18, 1283–1286 (2000).
Snell, K. & Peoples, O. Polyhydroxyalkanoate polymers and their production in transgenic plants. Metab. Eng. 4, 29–40 (2002).
Stafford, D.E. et al. Optimizing bioconversion pathways through systems analysis and metabolic engineering. Proc. Natl. Acad. Sci. USA 99, 1801–1806 (2002).
Stephanopoulos, G. & Kelleher, J. Biochemistry: how to make a superior cell. Science 292, 2024–2025 (2001).
Viswanathan, K. et al. Engineering sialic acid synthetic ability into insect cells: identifying metabolic bottlenecks and devising strategies to overcome them. Biochemistry 42, 15215–15225 (2003).
Xue, Y. & Sherman, D.H. Alternative modular polyketide synthase expression controls macrolactone structure. Nature 403, 571–575 (2000).
Askenazi, M. et al. Integrating transcriptional and metabolite profiles to direct the engineering of lovastatin-producing fungal strains. Nat. Biotechnol. 21, 150–156 (2003).
von Mering, C. et al. Comparative assessment of large-scale data sets of protein-protein interactions. Nature 417, 399–403 (2002).
Lee, T.I. et al. Transcriptional regulatory networks in Saccharomyces cerevisiae. Science 298, 799–804 (2002).
Shannon, P. et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 13, 2498–2504 (2003).
Ideker, T. et al. Integrated genomic and proteomic analyses of a systematically perturbed metabolic network. Science 292, 929–934 (2001).
Ideker, T., Ozier, O., Schwikowski, B. & Siegel, A.F. Discovering regulatory and signaling circuits in molecular interaction networks. Bioinformatics 18 (suppl. 1) 233–240 (2002).
Stephanopoulos, G., Hwang, D., Schmitt, W.A., Misra, J. & Stephanopoulos, G. Mapping physiological states from microarray expression measurements. Bioinformatics 18, 1054–1063 (2002).
Allen, J. et al. High-throughput classification of yeast mutants for functional genomics using metabolic footprinting. Nat. Biotechnol. 21, 692–696 (2003).
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We acknowledge the DuPont-MIT Alliance for research support and Kyle Jensen for his helpful suggestions.
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Stephanopoulos, G., Alper, H. & Moxley, J. Exploiting biological complexity for strain improvement through systems biology. Nat Biotechnol 22, 1261–1267 (2004). https://doi.org/10.1038/nbt1016
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DOI: https://doi.org/10.1038/nbt1016
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