Application of balancing methods in modeling the penicillin fermentation

Heijnen, J. J.; Roels, J. A.; Stouthamer, A. H.

doi:10.1002/bit.260211204

Cited by 110 publications

(48 citation statements)

References 17 publications

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“…(26), (27), and (28) after setting Gx = 0 (since there is no input or removal of biomass to and from the system) and V Gs = F(t), where F(t) is the relation expressing the total rate of substrate input as a function of time2: Thus, the conditions stated by eqs. (37) and (38) allows a very rapid and convenient determination procedure for the maintenance coefficient term m,.…”

Section: A Simple Unstructured Model For Microbial Growthmentioning

confidence: 98%

Theory and applications of unstructured growth models: Kinetic and energetic aspects

Esener

Roels

Kossen

1983

Biotech & Bioengineering

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Microbial kinetics and energetics are discussed in connection with the formulation of unstructured growth models. The development of microbial energetics and the use of macroscopic methods in the study of microbial growth are briefly evaluated. The general approach to the modelling of microbial growth has been critically discussed and a strategy for the formulation of unstructured models is presented. A simple unstructured model based on Monod kinetics and the linear relation for substrate consumption is evaluated with reference to extensive experimental and simulation data obtained in batch, fed-batch, and continuous cultivation modes. Choice for a kinetic expression is discussed and has been shown not to be critical in most situations. It is shown that during growth in batch mode, the behavior of the system is rigidly fixed by the kinetic parameter: the maximum specific growth rate. The energetic parameters have minimal influence. In continuous cultivation the behavior is fixed by the energetic parameters: the maximum yield and the coefficient of maintenance. Implications of these observations have also been discussed. The linear relation for substrate consumption is tested with continuous culture data. It is shown that significant deviations at low growth rates cannot be fully accounted by the loss of viability. The situations where unstructured models will be adequate or not for system description, are evaluated and checked experimentally. Influence of an environmental factor, the temperature, on the unstructured model parameters is also quantitatively described. It is concluded that the art of unstructured model building has already reached its maturity and that now much effort should be channelled into the development and verification of structured models.

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Section: A Simple Unstructured Model For Microbial Growthmentioning

confidence: 98%

Theory and applications of unstructured growth models: Kinetic and energetic aspects

Esener

Roels

Kossen

1983

Biotech & Bioengineering

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“…In comparison, the stoichiometric conversion of biosynthetic redox to energy has a ratio of 4 Hexp/NADPH. Since redox can be converted to energy, the ratio of the shadow prices must have a value above 4.…”

Section: Definition Of Metabolic Constraintsmentioning

confidence: 99%

Biochemical production capabilities of escherichia coli

Varma

Boesch

Palsson

1993

Biotech & Bioengineering

179

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Microbial metabolism provides at mechanism for the conversion of substrates into useful biochemicals. Utilization of microbes in industrial processes requires a modification of their natural metabolism in order to increase the efficiency of the desired conversion. Redirection of metabolic fluxes forms the basis of the newly defined field of metabolic engineering. In this study we use a flux balance based approach to study the biosynthesis of the 20 amino acids and 4 nucleotides as biochemical products. These amino acids and nucleotides are primary products of biosynthesis as well as important industrial products and precursors for the production of other biochemicals. The biosynthetic reactions of the bacterium Escherichia coli have been formulated into a metabolic network, and growth has been defined as a balanced drain on the metabolite pools corresponding to the cellular composition. Theoretical limits on the conversion of glucose, glycerol, and acetate substrates to biomass as well as the biochemical products have been computed. The substrate that results in the maximal carbon conversion to a particular product is identified. Criteria have been developed to identify metabolic constraints in the optimal solutions. The constraints of stoichiometry, energy, and redox have been determined in the conversions of glucose, glycerol, and acetate substrates into the biochemicals. Flux distributions corresponding to the maximal production of the biochemicals are presented. The goals of metabolic engineering are the optimal redirection of fluxes from generating biomass toward producing the desired biochemical. Optimal biomass generation is shown to decrease in a piecewise linear manner with increasing product formation. In some cases, synergy is observed between biochemical production and growth, leading to an increased overall carbon conversion. Balanced growth and product formation are important in a bioprocess, particularly for nonsecreted products.

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“…When the relationship between # and qp is known, this allows the calculation of the optimum growth-rate trajectory in the industrial fed-batch process (Heijnen et al 1979, de Hollander 1993. Both the specific rate of biomass formation (/z) and that of protein production (%) affect the overall productivity.…”

Section: Effect Of Growth Rate On Product Formationmentioning

confidence: 99%

Physiological and technological aspects of large-scale heterologous-protein production with yeasts

Hensing

Rouwenhorst

Heijnen

et al. 1995

Antonie van Leeuwenhoek

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138

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Commercial production of heterologous proteins by yeasts has gained considerable interest. Expression systems have been developed for Saccharomyces cerevisiae and a number of other yeasts. Generally, much attention is paid to the molecular aspects of heterologous-gene expression. The success of this approach is indicated by the high expression levels that have been obtained in shake-flask cultures. For large-scale production however, possibilities and restrictions related to host-strain physiology and fermentation technology also have to be considered. In this review, these physiological and technological aspects have been evaluated with the aid of numerical simulations. Factors that affect the choice of a carbon substrate for large-scale production involve price, purity and solubility. Since oxygen demand and heat production (which are closely linked) limit the attainable growth rate in large-scale processes, the biomass yield on oxygen is also a key parameter. Large-scale processes impose restrictions on the expression system. Many promoter systems that work well in small-scale systems cannot be implemented in industrial environments. Furthermore, large-scale fed-batch fermentations involve a substantial number of generations. Therefore, even low expression-cassette instability has a profound effect on the overall productivity of the system. Multicopy-integration systems may provide highly stable expression systems for industrial processes. Large-scale fed-batch processes are typically performed at a low growth rate. Therefore, effects of a low growth rate on the physiology and product formation rates of yeasts are of key importance. Due to the low growth rates in the industrial process, a substantial part of the substrate carbon is expended to meet maintenance-energy requirements. Factors that reduce maintenance-energy requirements will therefore have a positive effect on product yield. The relationship between specific growth rate and specific product formation rate (kg product-[kg biomass]-1.h-I) is the main factor influencing production levels in large-scale production processes. Expression systems characterized by a high specific rate of product formation at low specific growth rates are highly favourable for large-scale heterologous-protein production.

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Application of balancing methods in modeling the penicillin fermentation

Cited by 110 publications

References 17 publications

Theory and applications of unstructured growth models: Kinetic and energetic aspects

Theory and applications of unstructured growth models: Kinetic and energetic aspects

Biochemical production capabilities of escherichia coli

Physiological and technological aspects of large-scale heterologous-protein production with yeasts

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