Pires Sílvia D S, Oliveira Rute, Moradas-Ferreira Pedro, Mendes Marta V
i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal.
IBMC-Instituto de Biologia Molecular e Celular, Universidade do Porto, 4200-135 Porto, Portugal.
Antibiotics (Basel). 2020 Oct 15;9(10):703. doi: 10.3390/antibiotics9100703.
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 has been briefly acknowledged. Here, we investigate the impact of the oxidative stress response on tacrolimus biosynthesis in . Physiological characterization of 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, ∆ strain, a strain defective in the HO-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.
氧化应激反应是微生物适应不断变化的环境条件的关键机制。适应是通过一种微调的分子反应实现的，这种反应将其影响扩展到初级和次级代谢。过去，细胞内氧化还原状态在他克莫司生物合成中的作用已得到简要认可。在此，我们研究氧化应激反应对他克莫司生物合成的影响。对[具体对象]的生理特性研究表明，他克莫司生物合成的开始与过氧化氢酶活性的诱导同时发生。此外，他克莫司具有抗氧化特性，因此可控的氧化还原环境对其生物合成有益。此外，[具体菌株名称]∆菌株（一种在清除HO的酶AhpC方面有缺陷的菌株）显示出他克莫司产量增加。蛋白质组学和转录组学研究表明，他克莫司过量生产表型与代谢重排相关，导致他克莫司生物合成前体的可用性增加。总之，我们的结果表明，主要用于细胞生长的碳源可以通过调节氧化代谢以利于低氧化的细胞内环境，并将代谢通量重新导向增加生物合成前体的可用性来触发他克莫司的产生。
