Macrokinetic model for methylotrophic Pichia pastoris based on stoichiometric balance.

A macrokinetic model for Pichia pastoris expressing recombinant human serum albumin is proposed. The model describes the balances of some key metabolites, ATP and NADH, during glycerol and methanol metabolism. In the glycerol growth phase, the metabolic pathways mainly include phosphorylation, glycolysis, tricarboxylic acid cycle, and respiratory chain. In the methanol growth phase, methanol is oxidized to formaldehyde at first. Then, while a part of formaldehyde is oxidized to formate, the rest is condensed with xylulose-5-monophosphate to form glyceraldehyde-3-phosphate, and further assimilated to form cell constituents. The metabolic pathways following glyceraldehyde-3-phosphate were assumed to be similar to those in the glycerol growth phase. Based on the model, the macrokinetic bioreaction rates such as the specific substrate consumption rate, the specific growth rate, the specific acetyl-CoA formation rate as well as the specific oxygen uptake rate are obtained. The specific substrate consumption rate and the specific growth rate are then coupled into a bioreactor model such that the relationship between substrate feeding rates and the main state variables, i.e., the medium volume, the concentrations of the biomass, the substrate, and the product, is set up. Experimental results demonstrate that the model can describe the cell growth and the protein production with reasonable accuracy.

Process models for production of beta-lactam antibiotics.

Great progress has been made in the modelling of biotechnical processes using filamentous microorganisms. This paper deals with cultivations of Penicillium chrysogenum for the production of Penicillin and of Acremonium chrysogenum for the production of Cephalosporin C. The properties of the processes and the existing models are reviewed. Models are presented for both processes that consider aspects which are important for industrial cultivation. The process model for Penicillin production is based on a detailed morphological description of growth of hyphal filaments and pellets. The model allows for simulation of the production process including the preculture and considering the inhomogenous pellet population. It opens new possibilities for understanding the complex kinetics of the process and improvement of its control. The structured segregated model for Cephalosporin C production considers soy oil as second carbon source besides sugar. The application of the model for dynamic optimization of feeding strategies by Iterative Dynamic Programming is demonstrated. As an alternative approach, modelling of the Cephalosporin production by an artificial neural network is discussed.

Segregated mathematical model for the fed-batch cultivation of a high-producing strain of Penicillium chrysogenum.

A new segregated mathematical model for the penicillin fed-batch process is presented and applied to the growth of the pellet-forming, industrially used high-producing strain Penicillium chrysogenum S2. The model comprises two kinds of biomass (growing and producing, nongrowing and still producing), cell lysis, and complex medium as an important substrate for primary growth. In accordance with our experimental observation, product formation is not inhibited by glucose, but related to the growth rate. Maintenance metabolism is cell age-dependent. The model was verified with two sets of experimental data including exhaust gas measurements while keeping the estimated parameters almost constant. The presented model derived from that of Bajpai and Reuss (1980, 1981) does not describe our data properly. The particular influence of the pellet structure on the model is discussed. The necessity of new model assumptions (e.g., different kinds of biomass, non-constant maintenance coefficient) is explained by cell damage by lysis and shear forces, and the succeeding repair processes.

Model-based quality control of the baker's yeast Saccharomyces cerevisiae.

This paper deals with the optimal control of storage stability for compressed baker's yeast by minimizing the fraction of budding cells (FBC) based on a metabolic and cell cyclic model system for Saccharomyces cerevisiae. Three experiments of quality control were successfully carried out. The experimental data revealed that under optimal operation conditions, the final FBC-values approached the theoretical minimum and that storage stability was enhanced.

Profit optimization for baker's yeast fed-batch fermentation.

The model-based profit optimization for baker's yeast fed-batch fermentation was done in this paper. The model system used for simulation was a combined metabolic and cell cyclic model for baker's yeast Saccharomyces cerevisiae. The objective function was built according to cost-effect balances, while the required data came from a baker's yeast factory. The simulation of profit optimization revealed that in order to obtain the highest profit, there exist optimal operation regions for major manipulating variables, such as substrate feeding rate, sugar concentration in feed, aeration rate and fermentation period.