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

Pedro de N. Pissarra, Jens Bredal Nielsen, M. J. Bazin

    Research output: Contribution to journalJournal articleResearchpeer-review

    Abstract

    A kinetic model representing the pathway for the biosynthesis of penicillin by P. chrysogenum has been developed. The model is capable of describing the flux through the biosynthetic pathway, and model simulations correspond well with measurements of intermediates and end products. One feature of the present model structure is that it assumes the kinetics of the enzyme isopenicillin N synthetase (IPNS) to be first order with respect to the dissolved oxygen concentration in the range of 0.070 to 0.18 mM (25% to 70% saturation with air). Thus, it indicates the importance that molecular oxygen has on the rate of the reaction catalyzed by this enzyme, and consequently as an enhancer of the specific rate of penicillin production. Using the kinetic model, metabolic control analysis (MCA) of the pathway was performed. The determined flux control coefficients suggested that, during the production phase, the flux is controlled by IPNS as this enzyme becomes saturated with tripeptide delta-(L-alpha-amino-adipyl)-L-cysteinyl-D-valine (LLD-ACV). In the simulations, oxygen was shown to be a bottleneck alleviator by stimulating the rate of IPNS which prevents the accumulation of LLD-ACV. As a consequence of this stimulation, the rate-controlling step was moved to another place in the pathway.
    Original languageEnglish
    JournalBiotechnology and Bioengineering
    Volume51
    Issue number2
    Pages (from-to)168-176
    ISSN0006-3592
    DOIs
    Publication statusPublished - 1996

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