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In this study, to mimic industrial\u2010scale spatial DO gradients, we present a scale\u2010down setup based on dynamic feast\/famine regime (150\u2009s) that leads to repetitive cycles with rapid changes in DO availability in glucose\u2010limited chemostat cultures of <jats:italic>Penicillium chrysogenum<\/jats:italic>. Such DO feast\/famine regime induced a stable and repetitive pattern with a reproducible metabolic response in time, and the dynamic response of intracellular metabolites featured specific differences in terms of both coverage and magnitude in comparison to other dynamic conditions, for example, substrate feast\/famine cycles. Remarkably, intracellular sugar polyols were considerably increased as the hallmark metabolites along with a dynamic and higher redox state (NADH\/NAD<jats:sup>+<\/jats:sup>) of the cytosol. Despite the increased availability of NADPH for penicillin production under the oscillatory DO conditions, this positive effect may be counteracted by the decreased ATP supply. Moreover, it is interesting to note that not only the penicillin productivity was reduced under such oscillating DO conditions, but also that of the unrecyclable byproduct ortho\u2010hydroxyphenyl acetic acid\u00a0and degeneration of penicillin productivity. Furthermore, dynamic flux profiles showed the most pronounced variations in central carbon metabolism, amino acid (AA) metabolism, energy metabolism and fatty acid metabolism upon the DO oscillation. Taken together, the metabolic responses of <jats:italic>P. chrysogenum<\/jats:italic> to DO gradients reported here are important for elucidating metabolic regulation mechanisms, improving bioreactor design and scale\u2010up procedures as well as for constructing robust cell strains to cope with heterogenous industrial culture conditions.<\/jats:p>","DOI":"10.1002\/bit.28782","type":"journal-article","created":{"date-parts":[[2024,6,22]],"date-time":"2024-06-22T03:15:46Z","timestamp":1719026146000},"page":"3076-3098","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["An industrial perspective on metabolic responses of <i>Penicillium chrysogenum<\/i> to periodic dissolved oxygen feast\u2010famine cycles in a scale\u2010down system"],"prefix":"10.1002","volume":"121","author":[{"given":"Xueting","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Bioreactor Engineering East China 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