{
  "abstract": "Reprogramming biosynthetic assembly lines can extend biosynthesis beyond the chemical space explored by nature. However, this remains difficult because assembly-line function depends on coordinated interactions across large multidomain enzymes. Here, we couple gLM2, a genomic language model trained on metagenomic sequences, with discrete diffusion and domain-level conditioning to enable generative design and optimization of biosynthetic gene clusters. We apply this approach to a chimeric type I polyketide synthase (PKS) engineered to produce {delta}-valerolactam, a molecule not naturally synthesized by PKSs. Through iterative redesign of two multi-domain regions in the context of the full PKS sequence, gLM2 progressively improved {delta}-valerolactam production, yielding variants with up to 9.4-fold higher titer than the starting enzyme. Together, these results demonstrate that evolutionary sequence information can be learned and applied to complex, multi-domain enzyme design problems, expanding biosynthetic assembly lines to produce molecules outside their natural biosynthetic repertoire.",
  "abstract_shown": true,
  "affiliations": [
    "Tatta Bio"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 14,
  "authors": [
    {
      "name": "N. Lanclos"
    },
    {
      "name": "K. Ibrahim"
    },
    {
      "name": "A. Cornman"
    },
    {
      "name": "M. Huang"
    },
    {
      "name": "V. Gill"
    },
    {
      "name": "A. Jiang"
    },
    {
      "name": "J. Abraham"
    },
    {
      "name": "J. Gin"
    },
    {
      "name": "Y. Chen"
    },
    {
      "name": "C. Petzold"
    },
    {
      "name": "J. Baerwald"
    },
    {
      "name": "T. Kortemme"
    },
    {
      "name": "J. Keasling"
    },
    {
      "affs": [
        0
      ],
      "name": "Y. Hwang"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/dz8bw3dqc32zs.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.11.750945",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.11.750945v1.full",
  "id": "dz8bw3dqc32zs",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.11.750945v1",
  "language": null,
  "licence": "CC-BY-NC",
  "licence_label": "CC BY-NC",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "bioengineering"
    ],
    [
      "openalex",
      "2736|Microbial Natural Products and Biosynthesis"
    ]
  ],
  "openalex": "W7213551222",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.11.750945v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-11",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/dz8bw3dqc32zs.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:22:58Z",
      "native_id": "10.64898/2026.09.11.750945",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.11.750945v2"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:bioengineering",
      "subfield": "systems-synthetic"
    }
  ],
  "title": "Generative Design of New-to-nature Biosynthetic Assembly Lines with Genomic Language Modeling",
  "title_text": "Generative Design of New-to-nature Biosynthetic Assembly Lines with Genomic Language Modeling",
  "type": "preprint",
  "updated_at": "2026-10-30T12:23:39Z",
  "url": "https://research.draconitic.com/paper/dz8bw3dqc32zs",
  "venue": "bioRxiv",
  "versions": []
}