The oxidative stress response is a key mechanism that microorganisms have to adapt to changeling environmental conditions. Adaptation is achieved by a fine-tuned molecular response that extends its influence to primary and secondary metabolism. In the past, the role of the intracellular redox status in the biosynthesis of tacrolimus in Streptomyces tsukubaensis has been briefly acknowledged. Here, we investigate the impact of the oxidative stress response on tacrolimus biosynthesis in S. tsukubaensis. Physiological characterization of S. tsukubaensis showed that the onset of tacrolimus biosynthesis coincided with the induction of catalase activity. In addition, tacrolimus displays antioxidant properties and thus a controlled redox environment would be beneficial for its biosynthesis. In addition, S. tsukubaensis ∆ahpC strain, a strain defective in the H₂O₂-scavenging enzyme AhpC, showed increased production of tacrolimus. Proteomic and transcriptomic studies revealed that the tacrolimus over-production phenotype was correlated with a metabolic rewiring leading to increased availability of tacrolimus biosynthetic precursors. Altogether, our results suggest that the carbon source, mainly used for cell growth, can trigger the production of tacrolimus by modulating the oxidative metabolism to favour a low oxidizing intracellular environment and redirecting the metabolic flux towards the increase availability of biosynthetic precursors.

中文翻译：

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tsukubaensis链霉菌中他克莫司生物合成的开始取决于细胞内的氧化还原状态

氧化应激反应是微生物必须适应不断变化的环境条件的关键机制。适应是通过微调的分子反应实现的，该反应将其影响扩展到一级和二级代谢。过去，已经简单地认识到细胞内氧化还原状态在筑波链霉菌中他克莫司的生物合成中的作用。在这里，我们探讨他克莫司生物合成的氧化应激反应的影响S. tsukubaensis。筑波链球菌的生理特性结果表明他克莫司的生物合成开始与过氧化氢酶活性的诱导相吻合。此外，他克莫司显示出抗氧化特性，因此受控的氧化还原环境对其生物合成将是有益的。此外，S. tsukubaensis Δ AHPC应变，在H的应变缺陷₂ ö ₂-清除酶AhpC，显示他克莫司的产量增加。蛋白质组学和转录组学研究表明，他克莫司过量生产的表型与代谢重新布线相关，导致他克莫司生物合成前体的可用性增加。总而言之，我们的结果表明，主要用于细胞生长的碳源可通过调节氧化代谢以促进低氧化细胞内环境并使代谢通量转向增加生物合成前体的利用率，从而触发他克莫司的产生。