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<p>Engineered polyketide synthases (PKSs) have great potential as biocatalysts. These unnatural enzymes are capable of synthesizing molecules that are either not amenable to biosynthesis or are extremely challenging to access chemically. PKSs can thus be a powerful platform to expand the chemical landscape beyond the limits of conventional metabolic engineering. Here we employ a retrobiosynthesis approach to design and construct PKSs to produce δ-valerolactam (VL) and three enantiopure α-substituted VL analogues that have no known biosynthetic route. We introduce the engineered PKSs and pathways for various malonyl-CoA derivatives into <i>Pseudomonas putida</i> and use proteomics, metabolomics and culture condition optimization to improve the production of our target compounds. These α-substituted VLs are polymerized into polyamides (nylon-5) or converted into their <i>N</i>-acryloyl derivatives. RAFT polymerization produces bio-derived polymers with potential biomedical applications. Overall, this interdisciplinary effort highlights the versatility and effectiveness of a PKS-based retrobiosynthesis approach in exploring and developing innovative biomaterials.</p><p></p>

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Retrobiosynthesis of unnatural lactams via reprogrammed polyketide synthase

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年4月18日

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  • Namil Lee,
  • Matthias Schmidt,
  • Chenyi Li,
  • Connor J. Filbin,
  • Sarah Klass,
  • Allison Yaguchi,
  • Anna Lisa Fear,
  • Tyler W. H. Backman,
  • Brooks A. Abel,
  • Young-Mo Kim,
  • Woojoo E. Kim,
  • Christopher W. Johnson,
  • Yan Chen,
  • Jennifer W. Gin,
  • Christopher J. Petzold,
  • Edward E. K. Baidoo,
  • Yuqian Gao,
  • Meagan C. Burnet,
  • Gyorgy Babnigg,
  • Philip D. Laible,
  • Christine A. Singer,
  • William E. Michener,
  • Davinia Salvachúa,
  • Hector Garcia Martin,
  • Robert W. Haushalter,
  • Jay D. Keasling

摘要

Engineered polyketide synthases (PKSs) have great potential as biocatalysts. These unnatural enzymes are capable of synthesizing molecules that are either not amenable to biosynthesis or are extremely challenging to access chemically. PKSs can thus be a powerful platform to expand the chemical landscape beyond the limits of conventional metabolic engineering. Here we employ a retrobiosynthesis approach to design and construct PKSs to produce δ-valerolactam (VL) and three enantiopure α-substituted VL analogues that have no known biosynthetic route. We introduce the engineered PKSs and pathways for various malonyl-CoA derivatives into Pseudomonas putida and use proteomics, metabolomics and culture condition optimization to improve the production of our target compounds. These α-substituted VLs are polymerized into polyamides (nylon-5) or converted into their N-acryloyl derivatives. RAFT polymerization produces bio-derived polymers with potential biomedical applications. Overall, this interdisciplinary effort highlights the versatility and effectiveness of a PKS-based retrobiosynthesis approach in exploring and developing innovative biomaterials.