Pathway kinetics and metabolic control analysis of a high-yielding strain of Penicillium chrysogenum during fed batch cultivations

Pissara, Pedro de Noronha; Nielsen, Jens; Bazin, Michael J.

doi:10.1002/bit.260520502

Cited by 2 publications

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“…Bainbridge et al. reported a linear relationship between IPNS activity and the O 2 concentration within the range of 0.07 to 0.18 mmol L −1 [23], which was used in modeling studies [21, 22, 45]. However, at lower O 2 concentrations (<0.07 mmol L −1 ), the effect of DO on the rate of the IPNS enzyme has not yet been investigated.…”

Section: Resultsmentioning

confidence: 99%

“…Most modeling studies that describe the effect of DO on the penicillin pathway [21,22] rely on the finding from Bainbridge [23], which showed that the purified IPNS enzyme has a first order dependence on oxygen between 0.068 and 0.191 mmol L −1 DO. Modeling aspects on penicillin production are currently lacking solid evidence for the effect of DO levels below 0.068 mmol L −1 , and the assumed linearity might not be valid in a broader DO ranges.…”

Section: Practical Applicationmentioning

confidence: 99%

“…The activity of the second enzyme in the penicillin pathway, IPNS, is influenced directly by oxygen concentration because this step consumes molecular oxygen. Bainbridge et al reported a linear relationship between IPNS activity and the O 2 concentration within the range of 0.07 to 0.18 mmol L −1 [23], which was used in modeling studies [21,22,45]. However, at lower O 2 concentrations (<0.07 mmol L −1 ), the effect of DO on the rate of the IPNS enzyme has not yet been investigated.…”

Section: Modeling the Effect Of Omentioning

confidence: 99%

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Influence of oxygen concentration on the metabolism of Penicillium chrysogenum

Janoska

Verheijen

Tang

et al. 2022

Engineering in Life Sciences

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In large-scale bioreactors, there is often insufficient mixing and as a consequence, cells experience uneven substrate and oxygen levels that influence product formation. In this study, the influence of dissolved oxygen (DO) gradients on the primary and secondary metabolism of a high producing industrial strain of Penicillium chrysogenum was investigated. Within a wide range of DO concentrations, obtained under chemostat conditions, we observed different responses from P. chrysogenum: (i) no influence on growth or penicillin production (>0.025 mmol L −1 ); (ii) reduced penicillin production, but no growth limitation (0.013-0.025 mmol L −1 ); and (iii) growth and penicillin production limitations (<0.013 mmol L −1 ). In addition, scale down experiments were performed by oscillating the DO concentration in the bioreactor. We found that during DO oscillation, the penicillin production rate decreased below the value observed when a constant DO equal to the average oscillating DO value was used. To understand and predict the influence of oxygen levels on primary metabolism and penicillin production, we developed a black box model that was linked to a detailed kinetic model of the penicillin pathway. The model simulations represented the experimental data during the step experiments; however, during the oscillation experiments the predictions deviated, indicating the involvement of the central metabolism in penicillin production.

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Section: Resultsmentioning

confidence: 99%

Section: Practical Applicationmentioning

confidence: 99%

Section: Modeling the Effect Of Omentioning

confidence: 99%

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Influence of oxygen concentration on the metabolism of Penicillium chrysogenum

Janoska

Verheijen

Tang

et al. 2022

Engineering in Life Sciences

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“…Figure illustrates a simplified metabolic pathway model of penicillin V fermentation using Penicillium chrysogenum . The original mathematical model for this system was first constructed by Nielsen et al − This model was then extended and used to optimize a fed-batch fermentation process by Conejeros and Vassiliadis . The system contains both intracellular and extracellular metabolites.…”

Section: Theorymentioning

confidence: 99%

“…For this reason, dynamic sensitivity analysis is a useful tool for identifying bottlenecks at different stages of the processes being studied. In a previous work, Shiraishi and Suzuki performed a complete calculation of dynamic logarithmic gains over the entire period of a penicillin V fermentation process ,− and found that the ranking of the logarithmic gains changed with time, meaning that the ranking of bottleneck enzymes also changed with time. Therefore, the dynamic logarithmic gains of the penicillin V concentration in response to an infinitesimal percentage change in each enzyme activity were integrated over the entire fermentation period.…”

Section: Introductionmentioning

confidence: 99%

Instantaneous and Overall Indicators for Determination of Bottleneck Ranking in Metabolic Reaction Networks

Sriyudthsak

Shiraishi

2010

Ind. Eng. Chem. Res.

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A dynamic logarithmic gain expresses the percentage change in a dependent variable or metabolite concentration in response to an infinitesimal percentage change in an independent variable or enzyme activity. This article discusses the usefulness of several bottleneck ranking (BR) indicators that are functions of the logarithmic gain, to determine the most likely bottleneck enzyme in a dynamic metabolic reaction system. Mathematical models for penicillin V and ethanol fermentations are considered as case studies. The calculated results reveal that the instantaneous BR indicator, which is a product of the dynamic logarithmic gain and the metabolite concentration, is an effective measure for instantaneous bottleneck enzyme ranking changed during the fermentation period, whereas the overall BR indicator, which is a time-averaged value of the instantaneous BR indicator, is an effective measure for bottleneck enzyme ranking throughout the entire fermentation period.

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Pathway kinetics and metabolic control analysis of a high-yielding strain of Penicillium chrysogenum during fed batch cultivations

Cited by 2 publications

References 0 publications

Influence of oxygen concentration on the metabolism of Penicillium chrysogenum

Influence of oxygen concentration on the metabolism of Penicillium chrysogenum

Instantaneous and Overall Indicators for Determination of Bottleneck Ranking in Metabolic Reaction Networks

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