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

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

doi:10.1002/(sici)1097-0290(19960720)51:2<168::aid-bit6>3.0.co;2-h

Cited by 52 publications

(3 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The expected mechanism behind the decrease in q p was the decreased rate of IPNS enzyme due to oxygen limitation [ 23 ], which was apparent from the measured metabolite levels, where the IPNS concentration decreased while the intracellular ACV accumulated, both of which were most affected by the lowest DO level. These observations are in contrast to the measurements of Henriksen et al., who reported increased IPN concentrations under low DO concentrations of 0.019–0.344 mmol L −1 [ 15 ]; however, previous findings of ACV accumulation in the intra‐ and extracellular space is consistent our observations [ 15 , 21 ]. Our results suggested that at DO concentrations between 0.013 and 0.025 mmol L −1 , the IPN levels decrease to values that approach or fall below the Km values of the IAT and IAH enzymes, which reduce penicillin production.…”

Section: Discussioncontrasting

confidence: 71%

“…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: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Influence of oxygen concentration on the metabolism of Penicillium chrysogenum

Janoska

Verheijen

Tang

et al. 2022

Engineering in Life Sciences

View full text Add to dashboard Cite

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.

show abstract

Section: Discussioncontrasting

confidence: 71%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Influence of oxygen concentration on the metabolism of Penicillium chrysogenum

Janoska

Verheijen

Tang

et al. 2022

Engineering in Life Sciences

View full text Add to dashboard Cite

show abstract

Metabolic engineering: Techniques for analysis of targets for genetic manipulations

Nielsen

1998

Biotechnol. Bioeng.

Self Cite

142

View full text Add to dashboard Cite

Metabolic engineering has been defined as the purposeful modification of intermediary metabolism using recombinant DNA techniques. With this definition metabolic engineering includes: (1) inserting new pathways in microorganisms with the aim of producing novel metabolites, e.g., production of polyketides by Streptomyces; (2) production of heterologous peptides, e.g., production of human insulin, erythropoitin, and tPA; and (3) improvement of both new and existing processes, e.g., production of antibiotics and industrial enzymes. Metabolic engineering is a multidisciplinary approach, which involves input from chemical engineers, molecular biologists, biochemists, physiologists, and analytical chemists. Obviously, molecular biology is central in the production of novel products, as well as in the improvement of existing processes. However, in the latter case, input from other disciplines is pivotal in order to target the genetic modifications; with the rapid developments in molecular biology, progress in the field is likely to be limited by procedures to identify the optimal genetic changes. Identification of the optimal genetic changes often requires a meticulous mapping of the cellular metabolism at different operating conditions, and the application of metabolic engineering to process optimization is, therefore, expected mainly to have an impact on the improvement of processes where yield, productivity, and titer are important design factors, i.e., in the production of metabolites and industrial enzymes. Despite the prospect of obtaining major improvement through metabolic engineering, this approach is, however, not expected to completely replace the classical approach to strain improvement—random mutagenesis followed by screening. Identification of the optimal genetic changes for improvement of a given process requires analysis of the underlying mechanisms, at best, at the molecular level. To reveal these mechanisms a number of different techniques may be applied: (1) detailed physiological studies, (2) metabolic flux analysis (MFA), (3) metabolic control analysis (MCA), (4) thermodynamic analysis of pathways, and (5) kinetic modeling. In this article, these different techniques are discussed and their applications to the analysis of different processes are illustrated. © 1998 John Wiley & Sons, Inc. Biotechnol Bioeng 58:125–132, 1998.

show abstract

Dynamic biochemical reaction process analysis and pathway modification predictions

Conejeros

Vassiliadis

2000

Biotechnol. Bioeng.

View full text Add to dashboard Cite

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

Cited by 52 publications

References 22 publications

Influence of oxygen concentration on the metabolism of Penicillium chrysogenum

Influence of oxygen concentration on the metabolism of Penicillium chrysogenum

Metabolic engineering: Techniques for analysis of targets for genetic manipulations

Dynamic biochemical reaction process analysis and pathway modification predictions

Contact Info

Product

Resources

About