Application of dynamic flux balance analysis to an industrial Escherichia coli fermentation.
We have developed a reactor-scale model of Escherichia coli metabolism and growth in a 1000 L process for the production of a recombinant therapeutic protein. The model consists of two distinct parts: (1) a dynamic, process specific portion that describes the time evolution of 37 process variables of relevance and (2) a flux balance based, 123-reaction metabolic model of E. coli metabolism. This model combines several previously reported modeling approaches including a growth rate-dependent biomass composition, maximum growth rate objective function, and dynamic flux balancing. In addition, we introduce concentration-dependent boundary conditions of transport fluxes, dynamic maintenance demands, and a state-dependent cellular objective. This formulation was able to describe specific runs with high-fidelity over process conditions including rich media, simultaneous acetate and glucose consumption, glucose minimal media, and phosphate depleted media. Furthermore, the model accurately describes the effect of process perturbations--such as glucose overbatching and insufficient aeration--on growth, metabolism, and titer.
Meadows
Adam L
AL
Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. adameadows@gmail.com
Karnik
Rahi
R
Lam
Harry
H
Forestell
Sean
S
Snedecor
Brad
B
D000085:Acetates / Q000378:metabolism*; D000693:Anaerobiosis; D018533:Biomass; D019149:Bioreactors; D018929:Cell Culture Techniques; D003470:Culture Media / Q000378:metabolism; D004926:Escherichia coli / Q000254:growth & development / Q000378:metabolism*; D005285:Fermentation; D005947:Glucose / Q000378:metabolism*; D007218:Industrial Microbiology; D053858:Metabolic Networks and Pathways; D008954:Models, Biological
D000085:Acetates; D003470:Culture Media; D005947:Glucose