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Biotechnol Bioeng. 2011 Apr;108(4):934-46. doi: 10.1002/bit.22995. Epub 2010 Nov 26.

Fed-batch culture of Escherichia coli for L-valine production based on in silico flux response analysis.

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Metabolic and Biomolecular Engineering National Research Laboratory, Department of Chemical and Biomolecular Engineering, BK21 Program, KAIST, Daejeon 305-701, Republic of Korea.


We have previously reported the development of a 100% genetically defined engineered Escherichia coli strain capable of producing L-valine from glucose with a high yield of 0.38 g L-valine per gram glucose (0.58 mol L-valine per mol glucose) by batch culture. Here we report a systems biological strategy of employing flux response analysis in bioprocess development using L-valine production by fed-batch culture as an example. Through the systems-level analysis, the source of ATP was found to be important for efficient L-valine production. There existed a trade-off between L-valine production and biomass formation, which was optimized for the most efficient L-valine production. Furthermore, acetic acid feeding strategy was optimized based on flux response analysis. The final fed-batch cultivation strategy allowed production of 32.3 g/L L-valine, the highest concentration reported for E. coli. This approach of employing systems-level analysis of metabolic fluxes in developing fed-batch cultivation strategy would also be applicable in developing strategies for the efficient production of other bioproducts.

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