{
  "abstract": "Microbial metagenomes preserved in prehistoric dental calculus samples provide access to past bacterial biodiversity and evolutionary dynamics across archeological time scales. Consequently, this sequence space represents a largely unexplored resource for natural product discovery. Phylogeny-guided genome mining of human dental calculus metagenomes spanning recent times to the Middle and Upper Paleolithic revealed a distinct lasso cyclase lineage associated with oral Actinomyces species. Heterologous expression of a biosynthetic gene cluster reconstructed from an approximately 30,000-year-old sample yielded two lasso peptides, palassoptides A1 and A2. Structure analyses established a canonical class II lasso topology with an eight-residue macrolactam ring. Notably, both palassoptides feature an unprecedented amino acid composition for lasso peptides. Mutational analysis of the PalA2 precursor further showed that PalC accepts all possible substitutions at core position 1 except for Pro, revealing the broadest respective tolerance reported for a lasso cyclase to date. Homologous gene clusters with highly conserved yet variable precursor sequences are widespread among modern oral Actinomyces, indicating long-term preservation of this biosynthetic lineage within the human oral microbiome. The two palassoptides exhibited combination-dependent antibacterial activity against selected Gram-positive bacteria. These findings demonstrate that ancient metagenomes can reveal chemically uncharacterized natural products and expand the known structural diversity of natural products.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Paleobiotechnology, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, 07745Jena, Germany.",
    "Department of Pharmaceutical Sciences, University of Shizuoka, Shizuoka422-8526, Japan.",
    "Department of Archaeogenetics, Max Planck Institute for Evolutionary Anthropology, 04103Leipzig, Germany.",
    "Associated Research Group of Archaeogenetics, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, 07745Jena, Germany.",
    "Bio Pilot Plant, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, 07745Jena, Germany.",
    "Transfer Group Antiinfectives, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, 07745Jena, Germany.",
    "Department of Anthropology, Harvard University, Cambridge, Massachusetts02138, United States.",
    "Department of Human Evolutionary Biology, Harvard University, Cambridge, Massachusetts02138, United States.",
    "Cluster of Excellence Balance of the Microverse, Friedrich Schiller University Jena, Fürstengraben 1, 07743Jena, Germany.",
    "Institute of Organic Chemistry & Macromolecular Chemistry (IOMC), Friedrich Schiller University Jena, Humboldtstraße 10, 07743Jena, Germany."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 14,
  "authors": [
    {
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        0,
        1
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      "name": "Yusuke Hioki",
      "orcid": "0000-0002-7068-9654"
    },
    {
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        0
      ],
      "name": "Martin Klapper"
    },
    {
      "affs": [
        0
      ],
      "name": "Anan Ibrahim"
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    {
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        2,
        3
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      "name": "Alexander Hübner"
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        4
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      "name": "Matthias Steinacker"
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    {
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      "name": "Karsten Willing"
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    {
      "affs": [
        0
      ],
      "name": "Raed Nachawati"
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    {
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        0
      ],
      "name": "Daniela Hildebrandt"
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    {
      "affs": [
        0
      ],
      "name": "Lisa Reimer"
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    {
      "affs": [
        5
      ],
      "name": "Alina Zimmermann",
      "orcid": "0009-0003-1743-4489"
    },
    {
      "affs": [
        5
      ],
      "name": "Julia Mantke"
    },
    {
      "affs": [
        1
      ],
      "name": "Michio Sato",
      "orcid": "0000-0002-6026-8426"
    },
    {
      "affs": [
        2,
        3,
        6,
        7,
        8
      ],
      "name": "Christina Warinner",
      "orcid": "0000-0002-4528-5877"
    },
    {
      "affs": [
        0,
        8,
        9
      ],
      "name": "Pierre Stallforth",
      "orcid": "0000-0001-7260-9921"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/8yy90wrgcew73.bib",
  "cited_by": 0,
  "doi": "10.1021/jacs.6c14521",
  "fulltext_url": "https://europepmc.org/articles/PMC13632552",
  "id": "8yy90wrgcew73",
  "issns": [
    "0002-7863",
    "1520-5126"
  ],
  "landing_url": "https://europepmc.org/article/MED/42937876",
  "language": "eng",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2736|Microbial Natural Products and Biosynthesis"
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  "openalex": "W7213472462",
  "pdf_url": "https://europepmc.org/articles/PMC13632552?pdf=render",
  "pmcid": "PMC13632552",
  "pmid": "42937876",
  "published": "2026-09-01",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/8yy90wrgcew73.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:22:24Z",
      "native_id": "MED:42937876",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42937876"
    }
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  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2736|Microbial Natural Products and Biosynthesis",
      "subfield": "pharmacology-toxicology"
    }
  ],
  "title": "Reconstruction of a 30,000-Year-Old Biosynthetic Gene Cluster Reveals Lasso Peptides Formed by a Highly Tolerant Cyclase.",
  "title_text": "Reconstruction of a 30,000-Year-Old Biosynthetic Gene Cluster Reveals Lasso Peptides Formed by a Highly Tolerant Cyclase.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:22:24Z",
  "url": "https://research.draconitic.com/paper/8yy90wrgcew73",
  "venue": "Journal of the American Chemical Society",
  "versions": []
}