The Onset of Tacrolimus Biosynthesis in Streptomyces tsukubaensis Is Dependent on the Intracellular Redox Status

Pires, Sílvia D. S.; Oliveira, Rute; Moradas-Ferreira, Pedro; V. Mendes, Marta

doi:10.3390/antibiotics9100703

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The Onset of Tacrolimus Biosynthesis in Streptomyces tsukubaensis Is Dependent on the Intracellular Redox Status

Sílvia D. S. Pires

^1,2,†,‡,

Rute Oliveira

^1,2,3,†

Pedro Moradas-Ferreira

^1,2,4

and

Marta V. Mendes

^1,2,4,*

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

Programa doutoral em Biologia Molecular e Celular (MCBiology), ICBAS–Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, 4050-313 Porto, Portugal

⁴

ICBAS–Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, 4050-313 Porto, Portugal

Author to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

^‡

Present address: Jill Roberts Institute for IBD Research, Weill Cornell Medicine, New York, NY 10021, USA.

Antibiotics 2020, 9(10), 703; https://doi.org/10.3390/antibiotics9100703

Received: 15 August 2020 / Revised: 2 October 2020 / Accepted: 13 October 2020 / Published: 15 October 2020

(This article belongs to the Special Issue Contexts of Biosynthesis and Functions of the Antibiotics for the Producing Bacteria)

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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. View Full-Text

Keywords: Streptomyces; tacrolimus; oxidative stress; secondary metabolism

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MDPI and ACS Style

Pires, S.D.S.; Oliveira, R.; Moradas-Ferreira, P.; V. Mendes, M. The Onset of Tacrolimus Biosynthesis in Streptomyces tsukubaensis Is Dependent on the Intracellular Redox Status. Antibiotics 2020, 9, 703. https://doi.org/10.3390/antibiotics9100703

AMA Style

Pires SDS, Oliveira R, Moradas-Ferreira P, V. Mendes M. The Onset of Tacrolimus Biosynthesis in Streptomyces tsukubaensis Is Dependent on the Intracellular Redox Status. Antibiotics. 2020; 9(10):703. https://doi.org/10.3390/antibiotics9100703

Chicago/Turabian Style

Pires, Sílvia D.S., Rute Oliveira, Pedro Moradas-Ferreira, and Marta V. Mendes. 2020. "The Onset of Tacrolimus Biosynthesis in Streptomyces tsukubaensis Is Dependent on the Intracellular Redox Status" Antibiotics 9, no. 10: 703. https://doi.org/10.3390/antibiotics9100703

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The Onset of Tacrolimus Biosynthesis in Streptomyces tsukubaensis Is Dependent on the Intracellular Redox Status

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