Systems approaches to succinic acid-producing microorganisms
Abstract
Succinic acid is a cellular metabolite belonging to the C4-dicarboxylic acid family, and the fermentative production of succinic acid via the use of recombinant microorganisms has recently become the focus of an increasing amount of attention. Considering the difficulty inherent to the direct application of natural succinic acid producers to the industrial process, a variety of systems biology studies have been conducted regarding the development of enhanced succinic acid production systems. This review shows how the metabolic processes of microorganisms, includingEscherichia coli andMannheimia succiniciproducens, have been optimized in order to achieve enhanced succinic acid production. First, their metabolic networks were constructed on the basis of complete genome sequences, after which their metabolic characteristics were estimated viain silico computer modeling. Metabolic engineering strategies were designed in accordance with the results ofin silico modeling and metabolically engineered versions of bothE. coli andM. succiniciproducens have been constructed. The succinic acid productivity and yield obtained using metabolically engineered bacteria was significantly higher than that obtained using wild-type bacteria.
Keywords
succinic acid systems biology metabolic engineering metabolic characteristicsPreview
Unable to display preview. Download preview PDF.
References
- 1.Zeikus, J. G., and M. K. Jain, and P. Elankovan (1999) Biotechnology of succinic acid production and markets for derived industrial products.Appl. Microbiol. Biotechnol. 51: 545–552.CrossRefGoogle Scholar
- 2.Edwards, J. S., R. Ramakrishna, C. H. Schilling, and B. O. Palsson (1999) Metabolic flux balance analysis. pp. 13–57. In: S. Y. Lee and E. T. Papoutsakis (eds.):Metabolic Engineering. Marcel Dekker, New York, NY, USA.Google Scholar
- 3.Nielsen, J. and J. Villadsen (1994) Analysis of reaction rates, pp. 97–161. In: J. Nielsen and J. Villadsen (eds.),Bioreaction Engineering Principles, Plenum press, New York, NY, USA.Google Scholar
- 4.Lee, S. Y. and E. T. Papoutsakis (1999) The challenges and promise of metabolic engineering. pp. 1–12. In: S. Y. Lee and E. T. Papoutsakis (eds.):Metabolic Engineering. Marcel Dekker New York, NY, USA.Google Scholar
- 5.Lee, S.Y., D. Y. Lee, and T. Y. Kim (2005) Systems biotechnology for strain improvement.Trends Biotechnol. 23: 349–358.CrossRefGoogle Scholar
- 6.Jewett, M. C., A. P. Oliveira, K. R. Patil, and J. Nielsen (2005) The role of high-throughput transcriptome analysis in metabolic engineering.Biotechnol. Bioprocess Eng. 10: 385–399.CrossRefGoogle Scholar
- 7.Lee, S. Y., H. M. Woo, D.-Y. Lee, H. S. Choi, T. Y. Kim, and H. Yun (2005) Systems-level analysis of genome-scaleIn Silico metabolic models using Meta-FluxNet.Biotechnol. Bioprocess Eng. 10: 425–431.CrossRefGoogle Scholar
- 8.Jin, J. H. and J. Lee (2005)In Silico analysis of lactic acid secretion metabolism through the top-down approach: Effect of grouping in enzyme kinetics.Biotechnol. Bioprocess Eng., 10: 462–469.CrossRefGoogle Scholar
- 9.Bryant, M. P. and N. Small (1956) Characteristics of two new genera of anaerobic curved rods isolated from the rumen of cattle.J. Bacteriol. 72: 22–26.Google Scholar
- 10.Bryant, M. P., N. Small, C. Bouma, and H. Chu (1958)Bacteroides ruminicola n. sp. andSuccinimonas amylolytica the new genus and species: Species of succinic acid-producing anaerobic bacteria of the bovine rumen.J. Bacteriol. 76: 15–23.Google Scholar
- 11.Davis, C. P., D. Cleven, J. Brown, and E. Balish (1976)Anaerobiospirillum, a new genus of spiral-shaped bacteria.Int. J. Syst. Bacteriol. 26: 498–504.CrossRefGoogle Scholar
- 12.Guettler, M. V., D. Rumler, and M. K. Jain (1999)Actinobacillus succinogenes sp. nov. a novel succinic-acid-producing strain from the bovine rumen.Int. J. Syst. Bacteriol. 49: 207–216.Google Scholar
- 13.Scheifinger, C. C. and M. J. Wolin (1973) Propionate formation from cellulose and soluble sugars by combined cultures ofBacteroides succinogenes andSelenomonas ruminantium.Appl. Microbiol. 26: 789–795.Google Scholar
- 14.Van der Werf, M. J., M. V. Guettler, M. K. Jain, and J. G. Zeikus (1997) Environmental and physiological factors affecting the succinate product ratio during carbohydrate fermentation byActinobacillus sp. 130Z.Arch. Microbiol. 167: 332–342.CrossRefGoogle Scholar
- 15.Lee, P. C., W. G. Lee, S. Kwon, S. Y. Lee, and H. N. Chang (1999) Succinic acid production byAnaerobiospirillum succiniciproducens: Effects of the H2/CO2 supplying and glucose concentration.Enzyme. Microbiol. Technol. 24: 549–554.CrossRefGoogle Scholar
- 16.Samuelov, N. S., R. Lamed, S. Lowe and J. G. Zeikus (1991) Influence of CO2−HCO-levels and pH on growth, succinate production, and enzyme activities ofAnaerobiospirillum succiniciproducens.Appl. Environ. Microbiol. 57: 3013–3019.Google Scholar
- 17.Lee, P. C., W. G. Lee, S. Kwon, S. Y. Lee, and H. N. Chang (2000) Batch and continuous cultivation ofAnaerobiospirillum succiniproducens for the production of succinic acid from whey.Appl. Microbiol. Biotechnol. 54: 23–27.CrossRefGoogle Scholar
- 18.Guettler, M. V., M. K. Jain, and D. Rumler (1996) Method for making succinic acid, bacterial variants for use in the process, and methods for obtaining variants.US Patent 5,573,931.Google Scholar
- 19.Lee, P. C., S. Y. Lee, S. H. Hong, and H. N. Chang (2002) Isolation and characterization of a rew succinic acid-producing bacterium,Mannheimia succiniciproducens MBEL55E, from bovine rumen.Appl. Microbiol. Biotechnol. 58: 663–668.CrossRefGoogle Scholar
- 20.Millard, C. S., Y. P. Chao, J. C. Liao, and M. I. Donnelly (1996) Enhanced production of succinic acid by overexpression of phosphoenolpyruvate carboxylase inEscherichia coli.Appl. Environ. Microbiol. 62: 1808–1810.Google Scholar
- 21.Laivenieks, M., C. Vieille, and J. G. Zeikus (1997) Cloning, sequencing, and overexpression of theAnaerobiospirillum succiniciproducens phosphoenolpyruvate carboxykinase (pckA) gene.Appl. Environ. Microbiol. 63: 2273–2280.Google Scholar
- 22.Kwon, Y. D., S. Y. Lee, and P. Kim (2006) Influence of gluconeogenic phosphoenolpyruvate carboxykinase (PCK) expression on succinic acid fermentation inEscherichia coli under high bicarbonate condition.J. Microbiol. Biotechnol. 16: 1448–1452.Google Scholar
- 23.Kim, P., M. Laivenieks, C., Vieille and J. G. Zeikus (2004) Effect of overexpression ofActinobacillus succinogenes phosphoenolpyruvate carboxykinase on succinate production inEscherichia coli.Appl. Environ. Microbiol. 70: 1238–1241.CrossRefGoogle Scholar
- 24.Blattner, F. R., G. Plunkett, 3rd, C. A. Bloch, N. T. Perna, V. Burland, M. Riley, J. Collado-Vides, J. D. Glasner, C. K. Rode, G. F. Mayhew, J. Gregor, N. W. Davis, H. A. Kirkpatrick, M. A. Goeden, D. J. Rose, B. Mau, and Y. Shao (1997), The complete genome sequence ofEscherichia coli K-12.Science 277: 1453–1462.CrossRefGoogle Scholar
- 25.Burgard, A. P., S. Vaidyaraman, and C. D. Maranas (2001) Minimal reaction sets forEscherichia coli metabolism under different growth requirements and uptake environments.Biotechnol. Prog. 17: 791–797.CrossRefGoogle Scholar
- 26.Pramanik, J. and J. D. Keasling (1997) Stoichiometric model ofEscherichia coli metabolism: Incorporation of growth-rate dependent biomass composition and mechanistic energy requirements.Biotechnol. Bioeng. 56: 398–421.CrossRefGoogle Scholar
- 27.Stols, L. and M. I. Donnelly (1997) Production of succinic acid through overexpression of NAD(+)-dependent malic enzyme in anEscherichia coli mutant.Appl. Environ. Microbiol. 63: 2695–2701.Google Scholar
- 28.Stols, L., G. Kulkarni, B. G. Harris, and M. I. Donnelly (1997) Expression ofAscaris suum malic enzyme in a mutantEscherichia coli allows production of succinic acid from glucose.Appl. Biochem. Biotechnol. 63–65: 153–158.CrossRefGoogle Scholar
- 29.Hong, S. H. and S. Y. Lee (2001) Metabolic flux analysis for succinic acid production by recombinantEscherichia coli with amplified malic enzyme activity.Biotechnol. Bioeng. 74: 89–95.CrossRefGoogle Scholar
- 30.Hong, S. H. and S. Y. Lee (2004) Enhanced production of succinic acid by metabolically engineeredEscherichia coli with amplified activities of malic enzyme and fumarase.Biotechnol. Bioprocess Eng. 9: 252–255.CrossRefGoogle Scholar
- 31.Hong, S. H. and S. Y. Lee (2002) Importance of redox balance on the production of succinic acid by metabolically engineeredEscherichia coli.Appl. Microbiol. Biotechnol. 58: 286–290.CrossRefGoogle Scholar
- 32.Hong, S. H., S. Y. Moon, and S. Y. Lee (2003) Prediction of the maximum yields of metabolites and optimal pathways for their production by metabolic flux analysis.J. Microbiol. Biotechnol. 13: 571–577.Google Scholar
- 33.Lee, S. J., D.-Y. Lee, T. Y. Kim, B. H. Kim, J. Lee, and S. Y. Lee (2005) Metabolic engineering ofEscherichia coli for the enhanced production of succinic acid based on genome comparison andin silico gene knock-out simulation.Appl. Environ. Microbiol. 71: 7880–7887.CrossRefGoogle Scholar
- 34.Lin, H., G. N. Bennett, and K. Y. San (2005) Genetic reconstruction of the aerobic central metabolism inEscherichia coli for the absolute aerobic production of succinate.Biotechnol. Bioeng. 89: 148–156.CrossRefGoogle Scholar
- 35.Lin, H., G. N. Bennett, and K. Y. San (2005) Metabolic engineering of aerobic succinate production systems inEscherichia coli to improve process productivity and achieve the maximum theoretical succinate yield.Metab. Eng. 7: 116–127.CrossRefGoogle Scholar
- 36.Lin, H., G. N. Bennett, and K. Y. San (2005) Fed-batch culture of a metabolically engineeredEscherichia coli strain designed for high-level succinate production and yield under aerobic conditions.Biotechnol. Bioeng. 90: 775–779.CrossRefGoogle Scholar
- 37.Cox, S. J., S. Shalel Levanon, A. Sanchez, H. Lin, B. Peercy, G. N. Bennett, and K. Y. San (2006) Development of a metabolic network design and optimization framework incorporating implementation constraints: a succinate production case study.Metab. Eng. 8: 46–57.CrossRefGoogle Scholar
- 38.Sanchez, A. M., G. N. Bennett, and K. Y. San (2006) Batch culture characterization and metabolic flux analysis of succinate-producingEscherichia coli strains.Metab. Eng. 8: 209–226.CrossRefGoogle Scholar
- 39.Hong, S. H., J. S. Kim, S. Y. Lee, Y. H. In, S. S. Choi, J. K. Rih, C. H. Kim, H. Jeong, C. G. Hur, and J. J. Kim (2004) The genome sequence of the capnophilic rumen bacteriumMannheimia succiniciproducens.Nat. Biotechnol. 22: 1275–1281.CrossRefGoogle Scholar
- 40.Lee, S. J., H. Song, and S. Y. Lee (2006) Genome-based metabolic engineering ofMannheimia succiniciproducens for succinic acid production.Appl. Environ. Microbiol. 72: 1939–1948.CrossRefGoogle Scholar
- 41.Guettler, M. V. and M. K. Jain (1996) Method for making succinic acid,Anaerobiospirillum succiniciproducens variants for use in the process and methods for obtaining variants.US Patent 5,521,075.Google Scholar