While traveling through different zones in large‐scale bioreactors, microbes are most likely subjected to fluctuating dissolved oxygen (DO) conditions at the timescales of global circulation time. In this study, to mimic industrial‐scale spatial DO gradients, we present a scale‐down setup based on dynamic feast/famine regime (150 s) that leads to repetitive cycles with rapid changes in DO availability in glucose‐limited chemostat cultures of Penicillium chrysogenum. 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 nicotinamide adenine dinucleotide hydrogen/nicotinamide adenine dinucleotide 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 adenosine triphosphate 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‐hydroxyphenyl acetic acid and 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 P. chrysogenum to DO gradients reported here are important for elucidating metabolic regulation mechanisms, improving bioreactor design and scale‐up procedures as well as for constructing robust cell strains to cope with heterogenous industrial culture conditions.

中文翻译：

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从工业视角观察产黄青霉对缩小系统中周期性溶解氧盛宴-饥荒循环的代谢反应


在大型生物反应器中穿过不同区域时，微生物最有可能在全球循环时间尺度上受到波动的溶解氧（DO）条件的影响。在本研究中，为了模拟工业规模的空间 DO 梯度，我们提出了一种基于动态盛宴/饥荒状态（150 秒）的缩小设置，该设置导致重复循环，在青霉菌的葡萄糖限制恒化培养物中 DO 可用性快速变化chrysogenum。这种 DO 盛宴/饥荒状态诱导了稳定且重复的模式，并及时产生可重复的代谢反应，并且与其他动态条件（例如底物盛宴/饥荒）相比，细胞内代谢物的动态响应在覆盖范围和幅度方面具有特定差异。饥荒循环。值得注意的是，细胞内糖醇作为标志性代谢物以及细胞质的动态和较高氧化还原态烟酰胺腺嘌呤二核苷酸氢/烟酰胺腺嘌呤二核苷酸显着增加。尽管在振荡 DO 条件下，青霉素生产中 NADPH 的可用性增加，但这种积极作用可能会被三磷酸腺苷供应的减少所抵消。此外，有趣的是，在这种振荡的 DO 条件下，不仅青霉素的生产率降低了，而且不可回收的副产物邻羟基苯乙酸也降低了，青霉素生产率也下降了。此外，动态通量曲线显示了 DO 振荡时中心碳代谢、氨基酸（AA）代谢、能量代谢和脂肪酸代谢的最显着变化。总的来说，P 的代谢反应。 这里报道的 chrysogenum 到 DO 梯度对于阐明代谢调节机制、改进生物反应器设计和放大程序以及构建稳健的细胞株以应对异质工业培养条件非常重要。