{
  "abstract": "Directed evolution is widely used to enhance enzymatic performance and evolve new-to-nature reactivities, typically in vitro or in model microbial systems. However, variants selected in a model host may not retain their relative performance in the intended production organism. Here, we engineered a single 2-pyrone synthase (2PS) scaffold by directed evolution in Escherichia coli ( E. coli ) and evaluated the resulting variants in both E. coli and planta. In E. coli, engineered 2PS variants showed distinct chemoselectivities, giving access to precursors for kavalactones and raspberry ketone from one protein scaffold. The best variant achieved >98% conversion of p -coumaric acid to >200 µg/mL bisnoryangonin. In planta, however, variant performance was reordered: the top-performing microbial variant was outperformed 2.7-fold by one with lower activity in E. coli . We traced this host-dependent shift to competition for the shared p -coumaroyl-CoA pool and identified cinnamoyl-CoA reductase from Nicotiana benthamiana ( Nb CCR) as a key competing enzyme. Introducing Nb CCR into E. coli recapitulated the variant rank order observed in planta, demonstrating that metabolic competition can reshape the performance of engineered enzymes across hosts. These results also suggest that reconstructing key competing pathways of the target host in a tractable microbial system can provide a practical strategy for engineering enzymes for otherwise difficult-to-evolve production hosts. Finally, 2PS variants enabled the chemoenzymatic synthesis of natural and fluorinated kavalactones with up to 64% isolated yield over two steps.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Chemistry",
    "the University of Texas at Austin",
    "DOE Center for Advanced Bioenergy and Bioproducts Innovation",
    "University of Illinois at Urbana-Champaign",
    "Department of Molecular Biosciences"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 6,
  "authors": [
    {
      "affs": [
        0,
        1,
        2,
        3
      ],
      "name": "Yu Zhou",
      "orcid": "0000-0002-1882-9891"
    },
    {
      "affs": [
        4,
        1
      ],
      "name": "Zhengyao Shao",
      "orcid": "0000-0003-2965-8335"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Xueyi Xue",
      "orcid": "0000-0001-7918-5762"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Li-Qing Chen",
      "orcid": "0000-0002-0964-5388"
    },
    {
      "affs": [
        4,
        1
      ],
      "name": "Hong Qiao",
      "orcid": "0000-0003-3359-1962"
    },
    {
      "affs": [
        0,
        1,
        2,
        3
      ],
      "name": "Yi Lu",
      "orcid": "0000-0003-1221-6709"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/ew60jh7dshpmz.bib",
  "cited_by": 0,
  "doi": "10.26434/chemrxiv.15007623/v2",
  "fulltext_url": null,
  "id": "ew60jh7dshpmz",
  "issns": [],
  "landing_url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15007623/v2",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|Microbial Metabolic Engineering and Bioproduction"
    ]
  ],
  "openalex": "W7213342734",
  "pdf_url": "https://chemrxiv.org/doi/pdf/10.26434/chemrxiv.15007623/v2",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-15",
  "publisher": "American Chemical Society (ACS)",
  "ris": "https://research.draconitic.com/paper/ew60jh7dshpmz.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:19Z",
      "native_id": "10.26434/chemrxiv.15007623",
      "source": "chemrxiv",
      "url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15007623/v2"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Microbial Metabolic Engineering and Bioproduction",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Metabolic Competition Reshapes the Performance of Engineered Polyketide Synthases",
  "title_text": "Metabolic Competition Reshapes the Performance of Engineered Polyketide Synthases",
  "type": "preprint",
  "updated_at": "2026-10-30T12:17:19Z",
  "url": "https://research.draconitic.com/paper/ew60jh7dshpmz",
  "venue": "ChemRxiv",
  "versions": []
}