Development of a metabolic network design and optimization framework incorporating implementation constraints: A succinate production case study

Cox, Steven J.; Levanon, Sagit Shalel; Sánchez, Ailen M.; Lin, Henry; Peercy, Brad; Bennett, George N.; San, Ka‐Yiu

doi:10.1016/j.ymben.2005.09.006

Cited by 38 publications

(20 citation statements)

References 30 publications

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“…Operational constraints as well as any other limiting constraints (e.g. regulatory constraints) can easily be incorporated into the presented framework by reducing the set of active reactions or EMs (Cox et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

CASOP: A Computational Approach for Strain Optimization aiming at high Productivity

Hädicke

Klamt

2010

Journal of Biotechnology

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Section: Discussionmentioning

confidence: 99%

CASOP: A Computational Approach for Strain Optimization aiming at high Productivity

Hädicke

Klamt

2010

Journal of Biotechnology

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“…The glyoxylate shunt is an important pathway for anaerobic production of succinic acid (7,32). If succinate is produced exclusively via the reductive arm of the TCA cycle, only 1 mol of succinate is formed from 1 mol of glucose because only 2 mol of NADH is formed in glycolysis.…”

Section: Discussionmentioning

confidence: 99%

Improved Succinic Acid Production in the Anaerobic Culture of an Escherichia coli pflB ldhA Double Mutant as a Result of Enhanced Anaplerotic Activities in the Preceding Aerobic Culture

Zhou

et al. 2007

Appl Environ Microbiol

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Escherichia coli NZN111 is a pflB ldhA double mutant which loses its ability to ferment glucose anaerobically due to redox imbalance. In this study, two-stage culture of NZN111 was carried out for succinic acid production. It was found that when NZN111 was aerobically cultured on acetate, it regained the ability to ferment glucose with succinic acid as the major product in subsequent anaerobic culture. In two-stage culture carried out in flasks, succinic acid was produced at a level of 11.26 g/liter from 13.4 g/liter of glucose with a succinic acid yield of 1.28 mol/mol glucose and a productivity of 1.13 g/liter ⅐ h in the anaerobic stage. Analyses of key enzyme activities revealed that the activities of isocitrate lyase, malate dehydrogenase, malic enzyme, and phosphoenolpyruvate (PEP) carboxykinase were greatly enhanced while those of pyruvate kinase and PEP carboxylase were reduced in the acetate-grown cells. The two-stage culture was also performed in a 5-liter fermentor without separating the acetate-grown NZN111 cells from spent medium. The overall yield and concentration of succinic acid reached 1.13 mol/mol glucose and 28.2 g/liter, respectively, but the productivity of succinic acid in the anaerobic stage dropped to 0.7 g/liter ⅐ h due to cell autolysis and reduced anaplerotic activities. The results indicate the great potential to take advantage of cellular regulation mechanisms for improvement of succinic acid production by a metabolically engineered E. coli strain.

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“…These hypotheses include maximization of biomass formation (7), minimization of metabolic adjustment (MOMA) (8), regulatory on/off minimization (ROOM) (9) and ratio adjustment minimization (RAM) (10). These hypothesesdriven predictions have, in certain cases, been quite successful at recapitulating new fluxes after an environmental and/or genetic perturbation (11)(12)(13)(14). However, in the absence of any regulatory or mechanistic information the stoichiometry-based predictions are bound to be incomplete.…”

Section: Introductionmentioning

confidence: 99%

A Computational Procedure for Optimal Engineering Interventions Using Kinetic Models of Metabolism

Vital‐Lopez¹,

Armaou²,

Nikolaev³

et al. 2006

Biotechnol. Prog.

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The identification of optimal intervention strategies is a key step in designing microbial strains with enhanced capabilities. In this paper, we propose a general computational procedure to determine which genes/enzymes should be eliminated, repressed or overexpressed to maximize the flux through a product of interest for general kinetic models. The procedure relies on the generalized linearization of a kinetic description of the investigated metabolic system and the iterative application of mixed-integer linear programming (MILP) optimization to hierarchically identify all engineering interventions allowing for reaction eliminations and/or enzyme level modulations. The effect of the magnitude of the allowed changes in concentrations and enzyme levels is investigated, and a variant of the method to explore high-fold changes in enzyme levels is also analyzed. The proposed framework is demonstrated using a kinetic model modeling part of the central carbon metabolism of E. coli for serine overproduction. The proposed computational procedure is a general approach that can be applied to any metabolic system for which a kinetic description is provided.

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Development of a metabolic network design and optimization framework incorporating implementation constraints: A succinate production case study

Cited by 38 publications

References 30 publications

CASOP: A Computational Approach for Strain Optimization aiming at high Productivity

CASOP: A Computational Approach for Strain Optimization aiming at high Productivity

Improved Succinic Acid Production in the Anaerobic Culture of an Escherichia coli pflB ldhA Double Mutant as a Result of Enhanced Anaplerotic Activities in the Preceding Aerobic Culture

A Computational Procedure for Optimal Engineering Interventions Using Kinetic Models of Metabolism

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