Abstract
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.
Highlights
Members of the genus Streptomyces are amongst the most valuable industrial bacteria due to their ability to produce some of the most important classes of clinically active secondary metabolites [1]
Recent studies on the production of tacrolimus have suggested that the oxidative stress response might play a key role in modulating the production of tacrolimus in S. tsukubaensis [12,28]
Our results demonstrated that the intracellular redox status is an important factor for the production of tacrolimus in Stress responses are intricate molecular networks that allow microorganisms to adapt to challenging conditions via the rewiring of their metabolism
Summary
Members of the genus Streptomyces are amongst the most valuable industrial bacteria due to their ability to produce some of the most important classes of clinically active secondary metabolites [1]. Despite the high market value of tacrolimus and the growing industrial interest, the laboratory fermentation process of tacrolimus using wild type production strains often results in low yields. This has prompted several studies to improve the production of this compound, both in academia and industry. Metabolic engineering has been successfully used to reduce production costs and increase tacrolimus titres, through the manipulation of the genes involved in the biosynthetic process and precursors supply [12,13,14,15,16,17,18]. Manipulation of genes directly involved in primary metabolism can lead to a physiological imbalance and result in undesirable effects on growth rate [12]
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