Succinate Overproduction: A Case Study of Computational Strain Design Using a Comprehensive Escherichia coli Kinetic Model

Khodayari, Ali; Chowdhury, Anupam; Maranas, Costas D.

doi:10.3389/fbioe.2014.00076

Title: Succinate Overproduction: A Case Study of Computational Strain Design Using a Comprehensive Escherichia coli Kinetic Model

Journal Article · Mon Jan 05 00:00:00 EST 2015 · Frontiers in Bioengineering and Biotechnology

DOI:https://doi.org/10.3389/fbioe.2014.00076· OSTI ID:1629802

Khodayari, Ali ^[1]; Chowdhury, Anupam ^[1]; Maranas, Costas D. ^[1]

Pennsylvania State Univ., University Park, PA (United States). Dept. of Chemical Engineering

Computational strain-design prediction accuracy has been the focus for many recent efforts through the selective integration of kinetic information into metabolic models. In general, kinetic model prediction quality is determined by the range and scope of genetic and/or environmental perturbations used during parameterization. Here, we apply the k-OptForce procedure on a kinetic model of E. coli core metabolism constructed using the Ensemble Modeling (EM) method and parameterized using multiple mutant strains data under aerobic respiration with glucose as the carbon source. Minimal interventions are identified that improve succinate yield under both aerobic and anaerobic conditions to test the fidelity of model predictions under both genetic and environmental perturbations. Under aerobic condition, k-OptForce identifies interventions that match existing experimental strategies while pointing at a number of unexplored flux re-directions such as routing glyoxylate flux through the glycerate metabolism to improve succinate yield. Many of the identified interventions rely on the kinetic descriptions that would not be discoverable by a purely stoichiometric description. In contrast, under fermentative (anaerobic) condition, k-OptForce fails to identify key interventions including up-regulation of anaplerotic reactions and elimination of competitive fermentative products. This is due to the fact that the pathways activated under anaerobic condition were not properly parameterized as only aerobic flux data were used in the model construction. This study shed light on the importance of condition-specific model parameterization and provides insight on how to augment kinetic models so as to correctly respond to multiple environmental perturbations.

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Research Organization:: Pennsylvania State Univ., University Park, PA (United States)

Sponsoring Organization:: USDOE Office of Science (SC); National Science Foundation (NSF)

Grant/Contract Number:: SC0008091; EEC-0813570

OSTI ID:: 1629802

Journal Information:: Frontiers in Bioengineering and Biotechnology, Vol. 2; ISSN 2296-4185

Publisher:: Frontiers Research FoundationCopyright Statement

Country of Publication:: United States

Language:: English

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Title: Succinate Overproduction: A Case Study of Computational Strain Design Using a Comprehensive Escherichia coli Kinetic Model

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