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Brief Introduction to the Project on Systems Metabolic Engineering for Biorefineries
by Sang Yup Lee

Due to the increasing concerns on climate change, resource limitations and sustainability issues, and to reduce the dependence on fossil resources in petrochemical industry, there have been interests in developing bio-based chemical industry through establishing successful bio-refineries.

Microorganisms, corresponding to the chemical plant converting a raw material to a product of interest, have been increasingly employed for the production of chemicals, fuels and materials from non-food renewable biomass. Microorganisms isolated from Nature are inherently low in performance indices. Therefore, the metabolic and cellular networks have to be engineered to improve and to optimize its performance. Such metabolic engineering has been around for a little more than two decades, and it is being further advanced through the integration with other sub-disciplines such as systems biology, synthetic biology, and evolutionary engineering, resulting in the birth of systems metabolic engineering. We have been working on the project on developing platform technologies for the systems metabolic engineering of microorganisms for establishing successful bio-refineries through the research project funded by the Korean Ministry of Science, ICT and Future Planning (through National Research Foundation).

In the last three years of research in biorefineries, many platform technologies including genome-scale metabolic simulation tools, algorithms for systems-level optimal design of metabolic pathways, genome-wide engineering tools, rapid genome-engineering tools, and techno-economic evaluation tools [1-3]. Also, these platform technologies have been employed for the development of microbial strains capable of producing various products of industrial importance: carboxylic acids, dicarboxylic acids, amino acids, amino-carboxylic acids, higher alcohols, diols, diamines, polymers, and others including drugs [Figure 1; 4-14].

We have recently reported the general strategies for systems metabolic engineering for the development of industrially competitive microbial strains [15]. First, project is designed for the production of a particular bio-product of interest. Second, based on techno-economic analyses, a suitable host strain is selected. Third, metabolic pathways towards the production of the desired product are designed and constructed. Forth, tolerance to the product is increased. Fifth, regulatory circuits are engineered and rewired to open up the flux towards the formation of desired product, while byproducts formation is removed or reduced through the genome-wide scale pathway optimization, Sixth, cellular energy/redox levels and precursor availability are optimized at the systems-level through rerouting of the pathways if needed. Seventh, diagnosis of optimization of product formation. Eighth, microbial culture condition is optimized further. Ninth, systems-level genome engineering for further increase of product formation. And tenth, scale-up optimization of the entire process. Of course, these 10 strategies are employed in different sequences and in different combinations depending on the products of interest. Nonetheless, such strategies should be considered to improve the strain development process for successful bio-refineries [15]. More examples of products that are efficiently produced through bio-refineries are expected to appear by taking systems metabolic engineering approaches.

More recently, the Korean Ministry of Science, ICT and Future Planning is working on establishing an integrated program on “converting waste carbons to resources”, which will significantly contribute to decarbonizing fossil-based economy, and allow us to better cope with climate change problem. As recently suggested, proper collaboration between academia and industry, and at large all the stakeholders will be important to accomplish this goal [16]. It is expected that this project on the development of platform technologies for systems metabolic engineering for bio-refineries that provide us with engineering synergy [17] will contribute to achieving this important goal of our time.


This work was supported by the Technology Development Program to Solve Climate Changes on Systems Metabolic Engineering for Biorefineries (NRF-2012M1A2A2026556) from the Ministry of Science, ICT and Future Planning through National Research Foundation.


  1. Na, D., Yoo, S.M., Chung, H., Park, H., Park, J.H., and Lee, S.Y., "Metabolic engineering of Escherichia coli using synthetic small regulatory RNAs", Nature Biotechnol., 31(2): 170-174 (2013)
  2. Yoo, S.M., Na, D., Lee, S.Y., "Design and use of synthetic regulatory small RNAs to control gene expression in Escherichia coli", Nature Protoc., 8(9): 1694-1707 (2013)
  3. Kim, B., Kim, W.J., Kim, D. I., and Lee, S.Y., "Applications of genome-scale metabolic network model in metabolic engineering", J. Ind. Microbiol. Biotechnol. 42: 339–348 (2015)
  4. Chung, H., Yang, J.E., Ha, J.Y., Chae, T.U., Shin, J.H., Gustavsson, M., and Lee, S.Y. "Bio-based production of monomers and polymers by metabolically engineered microorganisms", Curr. Opin. Biotechnol, 36: 73-84 (2015)
  5. Cho, C., Jang, Y.-S., Moon, H.G., Lee, J., and Lee, S.Y., "Metabolic engineering of clostridia for the production of chemicals", Biofuels Bioprod. Bioref. 9(2): 211-225 (2015)
  6. Choi, S., Song, C.W., Shin, J.H., and Lee, S.Y.., "Biorefineries for the production of top building block chemicals and their derivatives", Metab. Eng., 28: 223-239 (2015)
  7. Lee, S.Y., Kim, H.M., and Cheon, S., "Metabolic engineering for the production of hydrocarbon fuels", Curr. Opin. Biotechnol, 33: 15-22 (2015)
  8. Choi, Y.J., Lee, J., Jang, Y.-S., and Lee, S.Y., "Metabolic engineering of microorganisms for the production of higher alcohols", mBio, 5(5): e01524-14, doi: 10.1128/mBio.01524-14 (2014)
  9. Choi, Y.J., Lee, S.Y., "Microbial production of short-chain alkanes", Nature, 502(7472): 571-574 (2013)
  10. Shin, J.H., Kim, H.U., Kim, D.I., and Lee, S.Y., "Production of bulk chemicals via novel metabolic pathways in microorganisms", Biotechnol. Adv., 31(6): 925-935 (2013)
  11. Jang, Y.-S., Kim, B., Shin, J.H., Choi, Y.J., Choi, S., Song, C.W., Lee, J., Park, H.G., Lee, S.Y. "Bio-based production of C2-C6 platform chemicals", Biotechnol. Bioeng. 109(10): 2437-2459 (2012)
  12. Kim, H.U., Ryu, J.Y., Lee, J.O. and Lee, S.Y., "A systems approach to traditional oriental medicine", Nature Biotechnol. 33:264-268 (2015)
  13. Weber, T., Charusanti, P., Musiol-Kroll, E.-W., Jiang, X., Tong, Y., Kim, H.U., and Lee, S.Y., "Metabolic engineering of antibiotic factories: new tools for antibiotic production in actinomycetes", Trends Biotechnol., 33(1): 15-26 (2015)
  14. Lee, J.W., Na, D., Park, J.M., Lee, J., Choi, S., and Lee, S.Y. "Systems metabolic engineering of microorganisms for natural and non-natural chemicals", Nature Chem. Biol. 8(6): 536-546 (2012)
  15. Lee, S.Y., Kim, H.U., "Systems strategies for developing industrial microbial strains", Nature Biotechnol., 33(10): 1061–1072 (2015)
  16. Pronk, J.T., Lee, S.Y., Lievense, J., Pierce, J., Palsson, B., Uhlen, M. and Nielsen, J., "How to set up collaborations between academia and industrial biotech companies", Nature Biotechnol. 33:237-240 (2015)
  17. Nielsen, J., Fussenegger, M., Keasling, J., Lee, S.Y., Liao, J.C., Prather, K. and Palsson, B., "Engineering synergy in biotechnology", Nature Chem. Biol., 10: 319-322 (2014)

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