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Applied and Environmental Microbiology, March 2006, p. 1939-1948, Vol. 72, No. 3
0099-2240/06/$08.00+0     doi:10.1128/AEM.72.3.1939-1948.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Genome-Based Metabolic Engineering of Mannheimia succiniciproducens for Succinic Acid Production{ddagger}

Sang Jun Lee,1,2,{dagger} Hyohak Song,1,{dagger} and Sang Yup Lee1,2,3*

Metabolic and Biomolecular Engineering National Research Laboratory, Department of Chemical and Biomolecular Engineering,1 Center for Ultramicrochemical Process Systems,2 Department of BioSystems, BioProcess Engineering Research Center and Bioinformatics Research Center, Korea Advanced Institute of Science and Technology, 373-1 Guseong-dong, Yuseong-gu, Daejeon 305-701, Republic of Korea3

Received 7 November 2005/ Accepted 3 January 2006

Succinic acid is a four-carbon dicarboxylic acid produced as one of the fermentation products of anaerobic metabolism. Based on the complete genome sequence of a capnophilic succinic acid-producing rumen bacterium, Mannheimia succiniciproducens, gene knockout studies were carried out to understand its anaerobic fermentative metabolism and consequently to develop a metabolically engineered strain capable of producing succinic acid without by-product formation. Among three different CO2-fixing metabolic reactions catalyzed by phosphoenolpyruvate (PEP) carboxykinase, PEP carboxylase, and malic enzyme, PEP carboxykinase was the most important for the anaerobic growth of M. succiniciproducens and succinic acid production. Oxaloacetate formed by carboxylation of PEP was found to be converted to succinic acid by three sequential reactions catalyzed by malate dehydrogenase, fumarase, and fumarate reductase. Major metabolic pathways leading to by-product formation were successfully removed by disrupting the ldhA, pflB, pta, and ackA genes. This metabolically engineered LPK7 strain was able to produce 13.4 g/liter of succinic acid from 20 g/liter glucose with little or no formation of acetic, formic, and lactic acids, resulting in a succinic acid yield of 0.97 mol succinic acid per mol glucose. Fed-batch culture of M. succiniciproducens LPK7 with intermittent glucose feeding allowed the production of 52.4 g/liter of succinic acid, with a succinic acid yield of 1.16 mol succinic acid per mol glucose and a succinic acid productivity of 1.8 g/liter/h, which should be useful for industrial production of succinic acid.

* Corresponding author. Mailing address: Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology, 373-1 Guseong-dong, Yuseong-gu, Daejeon 305-701, Republic of Korea. Phone: 82 42 869 3930. Fax: 82 42 869 3910. E-mail: leesy{at}kaist.ac.kr.

{ddagger} Supplemental material for this article can be found at http://aem.asm.org/.

{dagger} These authors contributed equally to this work.

Applied and Environmental Microbiology, March 2006, p. 1939-1948, Vol. 72, No. 3
0099-2240/06/$08.00+0     doi:10.1128/AEM.72.3.1939-1948.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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