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A highly active Burkholderia polyketoacyl-CoA thiolase for production of triacetic acid lactone

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  • Zilong Wang

    (Joint BioEnergy Institute
    University of California, Department of Chemical and Biomolecular Engineering
    University of California, QB3 Institute)

  • Seokjung Cheong

    (Joint BioEnergy Institute
    University of California, Department of Chemical and Biomolecular Engineering
    University of California, QB3 Institute)

  • Jose Henrique Pereira

    (Joint BioEnergy Institute
    Lawrence Berkeley National Laboratory, Molecular Biophysics & Integrated Bioimaging Division)

  • Weixi Hu

    (Joint BioEnergy Institute
    Berkeley, Department of Chemistry, University of California
    Berkeley, Department of Molecular and Cell Biology, University of California)

  • Yifan Guo

    (Joint BioEnergy Institute
    Berkeley, Department of Chemistry, University of California
    Berkeley, Department of Molecular and Cell Biology, University of California)

  • Andy DeGiovanni

    (Joint BioEnergy Institute
    Lawrence Berkeley National Laboratory, Molecular Biophysics & Integrated Bioimaging Division)

  • Guangxu Lan

    (Joint BioEnergy Institute
    Lawrence Berkeley National Laboratory, Biological Systems and Engineering Division)

  • Jinho Kim

    (Joint BioEnergy Institute
    Lawrence Berkeley National Laboratory, Biological Systems and Engineering Division)

  • Robert W. Haushalter

    (Joint BioEnergy Institute
    Lawrence Berkeley National Laboratory, Biological Systems and Engineering Division)

  • Taek Soon Lee

    (Joint BioEnergy Institute
    Lawrence Berkeley National Laboratory, Biological Systems and Engineering Division)

  • Paul D. Adams

    (Joint BioEnergy Institute
    Lawrence Berkeley National Laboratory, Molecular Biophysics & Integrated Bioimaging Division
    Berkeley, Department of Bioengineering, University of California)

  • Jay D. Keasling

    (Joint BioEnergy Institute
    University of California, Department of Chemical and Biomolecular Engineering
    Lawrence Berkeley National Laboratory, Biological Systems and Engineering Division
    Danish Technical University, Center for Biosustainability)

Abstract

Triacetic acid lactone (TAL) is a versatile platform chemical traditionally biosynthesized via decarboxylative Claisen condensation by 2-pyrone synthase. However, this route is limited by poor efficiency and dependence on malonyl-CoA. Here, we show that non-decarboxylative Claisen condensation by polyketoacyl-CoA thiolases offers a more efficient alternative. Through mining homologs of a previously reported enzyme from Cupriavidus necator, we identify five thiolases with TAL production activity. One candidate, BktBbr from Burkholderia sp. RF2-non_BP3, exhibits approximately 30-fold higher activity in vitro and supports 30-fold higher TAL titers in Escherichia coli compared to the original enzyme. Fed-batch fermentation achieves titers up to 2.8 g L⁻¹. Structural analysis of BktBbr co-crystallized with CoA esters guides rational engineering to further enhance performance. Our discovery of a highly active thiolase establishes an alternative enzymatic route to produce TAL efficiently, providing a scalable foundation for sustainable biomanufacturing.

Suggested Citation

  • Zilong Wang & Seokjung Cheong & Jose Henrique Pereira & Weixi Hu & Yifan Guo & Andy DeGiovanni & Guangxu Lan & Jinho Kim & Robert W. Haushalter & Taek Soon Lee & Paul D. Adams & Jay D. Keasling, 2025. "A highly active Burkholderia polyketoacyl-CoA thiolase for production of triacetic acid lactone," Nature Communications, Nature, vol. 16(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-65946-y
    DOI: 10.1038/s41467-025-65946-y
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