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Improving polyketide biosynthesis by rescuing the translation of truncated mRNAs into functional polyketide synthase subunits

Author

Listed:
  • Yan Liu

    (Shandong University)

  • Chaoyi Song

    (Shandong University)

  • Qingwen Cui

    (Shandong University)

  • Hongluan Sun

    (Shandong University)

  • Chanjuan Jiang

    (Shandong University)

  • Ruofei Guo

    (Shandong University)

  • Ruoting He

    (Shandong University)

  • Zhen Li

    (Shandong University)

  • Ji Luan

    (Shandong University)

  • Hailong Wang

    (Shandong University)

Abstract

Modular polyketide synthases (mPKSs) are multidomain enzymes in bacteria that synthesize a variety of pharmaceutically important compounds. mPKS genes are usually longer than 10 kb and organized in operons. To understand the transcriptional and translational characteristics of these large genes, here we split the 13-kb busA gene, encoding a 456-kDa three-module PKS for butenyl-spinosyn biosynthesis, into three smaller separately translated genes encoding one PKS module in an operon. Expression of the native and split busA genes in Streptomyces albus reveals that the majority ( >93%) of PKS mRNAs are truncated, resulting in a greater abundance of and a higher synthesis rate for the proteins encoded by genes closer to the operon promoter. Splitting the large busA gene rescues translation of truncated mRNAs into functional PKS subunits, and increases the biosynthetic efficiency of butenyl-spinosyn PKS by 13-fold. The truncated mRNA translation rescue strategy will facilitate engineering of multi-domain proteins to enhance their functions.

Suggested Citation

  • Yan Liu & Chaoyi Song & Qingwen Cui & Hongluan Sun & Chanjuan Jiang & Ruofei Guo & Ruoting He & Zhen Li & Ji Luan & Hailong Wang, 2025. "Improving polyketide biosynthesis by rescuing the translation of truncated mRNAs into functional polyketide synthase subunits," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-55973-0
    DOI: 10.1038/s41467-025-55973-0
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    References listed on IDEAS

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    1. Jianhua Li & Ishmael Mutanda & Kaibo Wang & Lei Yang & Jiawei Wang & Yong Wang, 2019. "Chloroplastic metabolic engineering coupled with isoprenoid pool enhancement for committed taxanes biosynthesis in Nicotiana benthamiana," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    2. Paul Huter & Claudia Müller & Bertrand Beckert & Stefan Arenz & Otto Berninghausen & Roland Beckmann & Daniel N. Wilson, 2017. "Structural basis for ArfA–RF2-mediated translation termination on mRNAs lacking stop codons," Nature, Nature, vol. 541(7638), pages 546-549, January.
    3. Somnath Dutta & Jonathan R. Whicher & Douglas A. Hansen & Wendi A. Hale & Joseph A. Chemler & Grady R. Congdon & Alison R. H. Narayan & Kristina Håkansson & David H. Sherman & Janet L. Smith & Georgio, 2014. "Structure of a modular polyketide synthase," Nature, Nature, vol. 510(7506), pages 512-517, June.
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