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Downloaded 10/9/2021 2:06:56 AM Chem Soc Rev View Article Online TUTORIAL REVIEW View Journal | View Issue Tools and strategies of systems metabolic engineering for the development of microbial cell Cite this: Chem. Soc. Rev., 2020, 49,4615 factories for chemical production Yoo-Sung Ko, †a Je Woong Kim, †a Jong An Lee, a Taehee Han, a Gi Bae Kim, a Jeong Eum Park a and Sang Yup Lee *abc Sustainable production of chemicals from renewable non-food biomass has become a promising alternative to overcome environmental issues caused by our heavy dependence on fossil resources. Systems metabolic engineering, which integrates traditional metabolic engineering with systems biology, synthetic biology, and evolutionary engineering, is enabling the development of microbial cell factories capable of efficiently producing a myriad of chemicals and materials including biofuels, bulk and fine chemicals, polymers, amino acids, natural products and drugs. In this paper, many tools and strategies of systems metabolic engineering, including in silico genome-scale metabolic simulation, sophisticated enzyme engineering, optimal gene expression modulation, in vivo biosensors, de novo pathway design, Received 23rd February 2020 and genomic engineering, employed for developing microbial cell factories are reviewed. Also, detailed DOI: 10.1039/d0cs00155d procedures of systems metabolic engineering used to develop microbial strains producing chemicals and materials are showcased. Finally, future challenges and perspectives in further advancing systems rsc.li/chem-soc-rev metabolic engineering and establishing biorefineries are discussed. Key learning points (1) Systems metabolic engineering, which integrates traditional metabolic engineering with systems biology, synthetic biology, and evolutionary engineering, accelerates the development of efficient microbial cell factories. Published on 22 June 2020. Downloaded 10/9/2021 2:06:56 AM. (2) Systems metabolic engineering considers upstream (raw material preparation), midstream (fermentation), and downstream (recovery and purification) processes together when developing microbial strains. (3) Through the integration of the tools and strategies of systems biology, genome-wide scale prediction of cellular status, including metabolic fluxes, is possible. (4) The use of synthetic biology tools allows the design and construction of enzymes and pathways for the production of more diverse chemicals and materials. (5) Evolutionary engineering allows enzymes, regulatory proteins, metabolic pathways, and/or entire cells to evolve to possess desired functions, characteristics, and/or phenotypes. 1. Introduction and such petrochemical products have brought unprecedented prosperity to humankind. However, we are now facing serious Numerous chemicals and materials around us are produced threats from the excessive use of fossil resources causing a from fossil resources through petrochemical refinery processes, climate crisis and environmental problems. Furthermore, fossil resources are not infinite, and will ultimately be depleted. To cope with these problems, it is essential to establish a a Metabolic and Biomolecular Engineering National Research Laboratory, Systems sustainable chemical industry capable of producing chemicals Metabolic Engineering and Systems Healthcare (SMESH) Cross-Generation Collaborative Laboratory, Department of Chemical and Biomolecular Engineering and materials from renewable non-edible biomass as a (BK21 Plus Program), Institute for the BioCentury, Korea Advanced Institute of raw material. For the bio-based production of chemicals and Science and Technology (KAIST), 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, materials, microorganisms are most often employed as they are Republic of Korea. E-mail: [email protected] ethically sound and can be securely cultured in a closed tank b Bioinformatics Research Center, KAIST, 291 Daehak-ro, Yuseong-gu, Daejeon, (e.g., a fermentor). Microbial production of chemicals and 34141, Republic of Korea c BioProcess Engineering Research Center, KAIST, 291 Daehak-ro, Yuseong-gu, materials is typically performed under mild conditions such Daejeon, 34141, Republic of Korea as relatively low temperature and pressure without using toxic † These authors contributed equally. solvents or metal catalysts, adding another set of advantages. This journal is © The Royal Society of Chemistry 2020 Chem. Soc. Rev., 2020, 49, 4615--4636 | 4615 View Article Online Tutorial Review Chem Soc Rev According to a recent report by Market Research Future in 2019, These objectives include enhanced production of a desired the global market size of bio-based chemicals is estimated to chemical or material, production of a novel chemical or grow with a CAGR of 10.47% to reach USD 97.2 billion by 2023. material that the wild-type strain has no metabolic capability For convenience, a biorefinery can be divided into four to biosynthesize, and degradation of a toxic or undesirable processes: the first upstream process that converts renewable chemical or material.2 Also, metabolic engineering can be biomass into fermentable carbohydrates, the second upstream performed to allow microorganisms to utilize the least expen- process that develops a microbial strain capable of efficiently sive carbon substrates available at the place of fermentation producing a desired product, the midstream process that operation. Furthermore, metabolic engineering is performed to cultivates microorganisms and produces a chemical or material reduce the production of byproducts, which consequently of interest, and the downstream process that recovers and facilitates the downstream processes and increases the yield purifies the desired product. Although none of these four of the product. processes is unimportant, the second upstream process of Over the past three decades, metabolic engineering has developing microbial strains is the most important as it deter- allowed the development of many different microbial strains mines the overall efficiency of converting raw material to a for the production of chemicals and materials. However, earlier product. Since microorganisms isolated from nature are not metabolic engineering research required a large amount of optimized for the production of our desired product, their manpower, time, and cost to develop industrially competitive performance needs to be enhanced. This is where metabolic microbial strains. More recently, systems metabolic engineering engineering comes into play. Metabolic engineering can be has been established through integrating traditional metabolic defined as the purposeful modification of cellular networks to engineering with the tools and strategies of systems biology, achieve defined objectives.1 synthetic biology, and evolutionary engineering for more efficient and rapid development of microbial cell factories. When devel- oping microbial strains by systems metabolic engineering (e.g., the second upstream process), it is extremely important to consider the first upstream, midstream, and downstream pro- Yoo-Sung Ko received his BS in cesses together for the overall optimization of the entire process Chemical and Biomolecular Engi- (Fig. 1).3 The advent of systems metabolic engineering promoted neering from Korea Advanced the development of high-performance strains producing various Institute of Science and Tech- bioproducts, including bulk chemicals, fine chemicals, polymers nology (KAIST) and currently is and materials, biofuels, and natural products (Fig. 1). Several of an Integrated MS/PhD candidate them, including lactic acid, polylactic acid (PLA), polyhydroxy- in Professor Sang Yup Lee’s Lab alkanoates (PHAs), succinic acid, ethanol, butanol, isobutanol, (Metabolic & Biomolecular 1,3-propanediol (1,3-PDO), 1,4-butanediol (1,4-BDO), isoprene, Engineering National Research farnesene, artemisinin, and various amino acids, have been Published on 22 June 2020. Downloaded 10/9/2021 2:06:56 AM. Laboratory) at KAIST. His commercialized or are close to commercialization.4 Also, some research focuses on the produc- biologically produced chemicalscanserveasplatformchemicals tion of industrial chemicals using andbefurtherconvertedintomany other valuable derivatives or Yoo-Sung Ko metabolically engineered bacteria polymers by integrating with chemical processes. A compre- through systems metabolic hensive map visualizing the strategies and pathways for the engineering. Je Woong Kim received his BS in Sang Yup Lee is a distinguished Chemical and Biomolecular Engi- professor at the Department of neering from Korea Advanced Chemical and Biomolecular Institute of Science and Tech- Engineering, Korea Advanced nology (KAIST) and currently is Institute of Science and Techno- an Integrated MS/PhD candidate logy (KAIST). He is currently the in Professor Sang Yup Lee’s Lab Dean of KAIST Institutes, Director (Metabolic & Biomolecular of BioProcess Engineering Research Engineering National Research Center, and Director of Bio- Laboratory) at KAIST. His informatics Research Center. His research focuses on the efficient research interests are metabolic production of industrial bulk engineering, systems and synthetic Je Woong Kim chemicals through metabolic Sang Yup Lee biology and biotechnology, engineering. industrial biotechnology, and nanobiotechnology. 4616 | Chem. Soc. Rev., 2020, 49, 4615--4636 This journal is © The Royal Society of Chemistry 2020 View Article Online Chem Soc Rev Tutorial Review Fig. 1 Overall strategies and procedures of systems metabolic engineering for the bio-based production of chemicals
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