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Peer-reviewedCC BY-NC-NDJournal of the American Chemical Society

Reconstruction of a 30,000-Year-Old Biosynthetic Gene Cluster Reveals Lasso Peptides Formed by a Highly Tolerant Cyclase.

  • Yusuke Hioki1,2
  • Martin Klapper1
  • Anan Ibrahim1
  • Alexander Hübner3,4
  • Matthias Steinacker5
  • Karsten Willing5
  • Raed Nachawati1
  • Daniela Hildebrandt1
  • Lisa Reimer1
  • Alina Zimmermann6
  • Julia Mantke6
  • Michio Sato2
2 more authors
  • Christina Warinner3,4,7,8,9
  • Pierre Stallforth1,9,10
10 affiliations
  1. 1Department of Paleobiotechnology, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, 07745Jena, Germany.
  2. 2Department of Pharmaceutical Sciences, University of Shizuoka, Shizuoka422-8526, Japan.
  3. 3Department of Archaeogenetics, Max Planck Institute for Evolutionary Anthropology, 04103Leipzig, Germany.
  4. 4Associated Research Group of Archaeogenetics, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, 07745Jena, Germany.
  5. 5Bio Pilot Plant, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, 07745Jena, Germany.
  6. 6Transfer Group Antiinfectives, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, 07745Jena, Germany.
  7. 7Department of Anthropology, Harvard University, Cambridge, Massachusetts02138, United States.
  8. 8Department of Human Evolutionary Biology, Harvard University, Cambridge, Massachusetts02138, United States.
  9. 9Cluster of Excellence Balance of the Microverse, Friedrich Schiller University Jena, Fürstengraben 1, 07743Jena, Germany.
  10. 10Institute of Organic Chemistry & Macromolecular Chemistry (IOMC), Friedrich Schiller University Jena, Humboldtstraße 10, 07743Jena, Germany.
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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.

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Cite

BibTeXRIS
BibTeX
@article{hioki2026reconstruction,
  title = {{Reconstruction of a 30,000-Year-Old Biosynthetic Gene Cluster Reveals Lasso Peptides Formed by a Highly Tolerant Cyclase.}},
  author = {Yusuke Hioki and Martin Klapper and Anan Ibrahim and Alexander Hübner and Matthias Steinacker and Karsten Willing and Raed Nachawati and Daniela Hildebrandt and Lisa Reimer and Alina Zimmermann and Julia Mantke and Michio Sato and Christina Warinner and Pierre Stallforth},
  journal = {Journal of the American Chemical Society},
  year = {2026},
  month = sep,
  doi = {10.1021/jacs.6c14521},
  url = {https://europepmc.org/article/MED/42937876},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Reconstruction of a 30,000-Year-Old Biosynthetic Gene Cluster Reveals Lasso Peptides Formed by a Highly Tolerant Cyclase.
AU  - Yusuke Hioki
AU  - Martin Klapper
AU  - Anan Ibrahim
AU  - Alexander Hübner
AU  - Matthias Steinacker
AU  - Karsten Willing
AU  - Raed Nachawati
AU  - Daniela Hildebrandt
AU  - Lisa Reimer
AU  - Alina Zimmermann
AU  - Julia Mantke
AU  - Michio Sato
AU  - Christina Warinner
AU  - Pierre Stallforth
PY  - 2026
DA  - 2026/09/01
JO  - Journal of the American Chemical Society
DO  - 10.1021/jacs.6c14521
UR  - https://europepmc.org/article/MED/42937876
AB  - 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.
SN  - 0002-7863
SN  - 1520-5126
ER  -