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EcoSal Plus

Domain 10: Bioinformatics and Systems Biology

Systems Metabolic Engineering of

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.
  • Authors: Kyeong Rok Choi1, Jae Ho Shin2, Jae Sung Cho3, Dongsoo Yang4, and Sang Yup Lee5,6,7
  • Editor: Peter D. Karp8
    Affiliations: 1: Metabolic and Biomolecular Engineering National Research Laboratory, Department of Chemical and Biomolecular Engineering (BK21 Plus Program), Center for Systems and Synthetic Biotechnology, Institute for the BioCentury, KAIST, Daejeon 34141, Republic of Korea; 2: Metabolic and Biomolecular Engineering National Research Laboratory, Department of Chemical and Biomolecular Engineering (BK21 Plus Program), Center for Systems and Synthetic Biotechnology, Institute for the BioCentury, KAIST, Daejeon 34141, Republic of Korea; 3: Metabolic and Biomolecular Engineering National Research Laboratory, Department of Chemical and Biomolecular Engineering (BK21 Plus Program), Center for Systems and Synthetic Biotechnology, Institute for the BioCentury, KAIST, Daejeon 34141, Republic of Korea; 4: Metabolic and Biomolecular Engineering National Research Laboratory, Department of Chemical and Biomolecular Engineering (BK21 Plus Program), Center for Systems and Synthetic Biotechnology, Institute for the BioCentury, KAIST, Daejeon 34141, Republic of Korea; 5: Metabolic and Biomolecular Engineering National Research Laboratory, Department of Chemical and Biomolecular Engineering (BK21 Plus Program), Center for Systems and Synthetic Biotechnology, Institute for the BioCentury, KAIST, Daejeon 34141, Republic of Korea; 6: BioProcess Engineering Research Center, KAIST, Daejeon 34141, Republic of Korea; 7: BioInformatics Research Center, KAIST, Daejeon 34141, Republic of Korea; 8: SRI International, Menlo Park, CA
  • Received 14 June 2015 Accepted 18 December 2015 Published 11 March 2016
  • Address correspondence to Sang Yup Lee [email protected]
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  • Abstract:

    Systems metabolic engineering, which recently emerged as metabolic engineering integrated with systems biology, synthetic biology, and evolutionary engineering, allows engineering of microorganisms on a systemic level for the production of valuable chemicals far beyond its native capabilities. Here, we review the strategies for systems metabolic engineering and particularly its applications in . First, we cover the various tools developed for genetic manipulation in to increase the production titers of desired chemicals. Next, we detail the strategies for systems metabolic engineering in , covering the engineering of the native metabolism, the expansion of metabolism with synthetic pathways, and the process engineering aspects undertaken to achieve higher production titers of desired chemicals. Finally, we examine a couple of notable products as case studies produced in strains developed by systems metabolic engineering. The large portfolio of chemical products successfully produced by engineered listed here demonstrates the sheer capacity of what can be envisioned and achieved with respect to microbial production of chemicals. Systems metabolic engineering is no longer in its infancy; it is now widely employed and is also positioned to further embrace next-generation interdisciplinary principles and innovation for its upgrade. Systems metabolic engineering will play increasingly important roles in developing industrial strains including that are capable of efficiently producing natural and nonnatural chemicals and materials from renewable nonfood biomass.

  • Citation: Choi K, Shin J, Cho J, Yang D, Lee S. 2016. Systems Metabolic Engineering of , EcoSal Plus 2016; doi:10.1128/ecosalplus.ESP-0010-2015


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Systems metabolic engineering, which recently emerged as metabolic engineering integrated with systems biology, synthetic biology, and evolutionary engineering, allows engineering of microorganisms on a systemic level for the production of valuable chemicals far beyond its native capabilities. Here, we review the strategies for systems metabolic engineering and particularly its applications in . First, we cover the various tools developed for genetic manipulation in to increase the production titers of desired chemicals. Next, we detail the strategies for systems metabolic engineering in , covering the engineering of the native metabolism, the expansion of metabolism with synthetic pathways, and the process engineering aspects undertaken to achieve higher production titers of desired chemicals. Finally, we examine a couple of notable products as case studies produced in strains developed by systems metabolic engineering. The large portfolio of chemical products successfully produced by engineered listed here demonstrates the sheer capacity of what can be envisioned and achieved with respect to microbial production of chemicals. Systems metabolic engineering is no longer in its infancy; it is now widely employed and is also positioned to further embrace next-generation interdisciplinary principles and innovation for its upgrade. Systems metabolic engineering will play increasingly important roles in developing industrial strains including that are capable of efficiently producing natural and nonnatural chemicals and materials from renewable nonfood biomass.

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Image of Figure 1
Figure 1

Systems metabolic engineering is the recursive process of improving a candidate strain via pathway engineering, transporter engineering, omics tools, and analysis in an effort to increase the production of desired chemicals to industrial scales.

Citation: Choi K, Shin J, Cho J, Yang D, Lee S. 2016. Systems Metabolic Engineering of , EcoSal Plus 2016; doi:10.1128/ecosalplus.ESP-0010-2015
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Image of Figure 2
Figure 2

List of tools for genetic modification of candidate strains: recombineering, zinc finger nuclease (ZFN), transcription activator-like effector nuclease (TALEN), clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system, global transcription machinery engineering (gTME), omics-based tools, multiplex automated genome engineering (MAGE), synthetic small regulatory RNA (sRNA), and scaffold proteins.

Citation: Choi K, Shin J, Cho J, Yang D, Lee S. 2016. Systems Metabolic Engineering of , EcoSal Plus 2016; doi:10.1128/ecosalplus.ESP-0010-2015
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Image of Figure 3
Figure 3

The endogenous metabolic pathway of mapping products (metabolites in black boxes and amino acids in turquoise boxes) and the genes (italicized) of the enzymes responsible for the reactions based on EcoCyc database. Every overexpression (blue circle), downregulation (red circle), and all other miscellaneous modifications including feedback-release (asterisk) attempted in for systems metabolic engineering purposes are noted. Convergence and divergence of metabolites are denoted by circular nodes, where some reactions are reversible. As an example for reversible reaction, F6P and GAP converge to form E4P and Xu5P; conversely, E4P and Xu5P converge to form F6P and GAP. Glc, glucose; G6P, glucose 6-phosphate; F6P, fructose 6-phosphate; F1,6BP, fructose 1,6-bisphosphate; GAP, glyceraldehyde 3-phosphate; DHAP, dihydroxyacetone phosphate; 1,3-BPG, 1,3-bisphosphoglycerate; 3-PG, 3-phosphoglycerate; 2-PG, 2-phosphoglycerate; PEP, phosphoenolpyruvate; PYR, pyruvate; Ac-CoA, acetyl-CoA; CIT, citrate; I-CIT, isocitrate; α-KG, α-ketoglutarate; SUCC-CoA, succinyl-CoA; SUCC, succinate; FUM, fumarate; MAL, malate; OAA, oxaloacetate; GOX, glyoxylate; E4P, erythrose 4-phosphate; Xu5P, xylulose 5-phosphate; S7P, sedoheptulose 7-phosphate; R5P, ribose 5-phosphate; Ru5P, ribulose 5-phosphate; RuBP, ribulose 1,5-bisphosphate; PRPP, 5-phosphoribose 1-pyrophosphate; AICAR, 5-amino-1-(5-phosphoribosyl)imidazole-4-carboxamide; His, -histidine; DAHP, 3-deoxy-arabino-heptulosonate 7-phosphate; DHQ, 3-dehydroquinate; DHS, dehydroshikimate; SHIK, shikimate; CHOR, chorismate; PPHN, prephenate; HPP, 4-hydroxyphenylpyruvate; Tyr, -tyrosine; PHPYR, phenylpyruvate; Phe, -phenylalanine; ANTH, anthranilate; Trp, -tryptophan; 3-PH, 3-phosphohydroxypyruvate; P-Ser, 3-phosphoserine; Ser, -serine; Ac-Ser, acetyl-serine; AcLAC, acetolactate; Val, -valine; Leu, -leucine; Ala, -alanine; -Ala, -alanine; Ac-P, acetyl phosphate; AcAc-CoA, acetoacetyl-CoA; Glu, -glutamate; Gln, -glutamine; Arg, -arginine; Pro, -proline; Asp, -aspartate; Asn, -asparagine; AspSA, aspartate-semialdehyde; Lys, -lysine; HMS, homoserine; Thr, -threonine; Ile, -isoleucine; SUCC-HMS, succinylhomoserine; CYST, cystathionine; HMC, homocysteine; Met, L-methionine; Ac-ACP, acetyl-acyl carrier protein (ACP); Mal-CoA, malonyl-CoA; Mal-ACP, malonyl-ACP; AcAc-ACP, acetoacetyl-ACP.

Citation: Choi K, Shin J, Cho J, Yang D, Lee S. 2016. Systems Metabolic Engineering of , EcoSal Plus 2016; doi:10.1128/ecosalplus.ESP-0010-2015