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Genomics-driven discovery of the biosynthetic gene cluster of maduramicin and its overproduction in Actinomadura sp. J1-007

  • Genetics and Molecular Biology of Industrial Organisms - Original Paper
  • Published:
Journal of Industrial Microbiology & Biotechnology

Abstract

Maduramicin is the most efficient and possesses the largest market share of all anti-coccidiosis polyether antibiotics (ionophore); however, its biosynthetic gene cluster (BGC) has yet to been identified, and the associated strains have not been genetically engineered. Herein, we performed whole-genome sequencing of a maduramicin-producing industrial strain of Actinomadura sp. J1-007 and identified its BGC. Additionally, we analyzed the identified BGCs in silico to predict the biosynthetic pathway of maduramicin. We then developed a conjugation method for the non-spore-forming Actinomadura sp. J1-007, consisting of a site-specific integration method for gene overexpression. The maduramicin titer increased by 30% to 7.16 g/L in shake-flask fermentation following overexpression of type II thioesterase MadTE that is the highest titer at present. Our findings provide insights into the biosynthetic mechanism of polyethers and provide a platform for the metabolic engineering of maduramicin-producing microorganisms for overproduction and development of maduramicin analogs in the future.

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Abbreviations

BGC:

Biosynthetic gene cluster

PKS:

Polyketide synthase

ORF:

Open reading frame

T1PKS:

Type I polyketide synthase

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Acknowledgements

This work was supported by funding from National Key R&D Program of China 2018YFA0900400, Hubei Natural Science Fund Project 2017CFA054, and J1 Biotech Co., Ltd.

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Authors and Affiliations

  1. Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education and Wuhan University School of Pharmaceutical Sciences, Wuhan, 430071, China

    Ran Liu, Fang Fang, Ziheng An, Renqiong Huang, Yong Wang, **ao Sun, Aisi Fu, Zixin Deng & Tiangang Liu

  2. J1 Biotech Co., Ltd, Wuhan, 430075, China

    Shuai Fu

  3. State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic and Developmental Sciences, and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200030, China

    Zixin Deng

  4. Hubei Engineering Laboratory for Synthetic Microbiology, Wuhan Institute of Biotechnology, Wuhan, 430075, China

    Zixin Deng & Tiangang Liu

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  1. Ran Liu
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Liu, R., Fang, F., An, Z. et al. Genomics-driven discovery of the biosynthetic gene cluster of maduramicin and its overproduction in Actinomadura sp. J1-007. J Ind Microbiol Biotechnol 47, 275–285 (2020). https://doi.org/10.1007/s10295-019-02256-5

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