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May 9, 2026Journal of Natural Products0 citationsOpen Access

Parallel Pathways and Alternative Macrocyclizations in the Biosynthesis of Largimycins by Cytochrome P450 Minus Mutants of Streptomyces argillaceus

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ABAdriana BecerrilIPIgnacio Pérez‐VictoriaJMJesús Martín

Key Points

  • The aim is to explore the biosynthesis pathways of largimycins and identify structural diversity resulting from cytochrome P450 minus mutations.
  • Investigated hydrolytic dehalogenation prior to peptide-polyketide chain off-loading
  • Analyzed compounds produced by LrgJ mutants for unique structural characteristics
  • Explored macrocyclization mechanisms and their impact on structural outcomes
  • Identified a unique β-thiolactone ring in compounds from mutants, not previously observed in natural products.
  • Revealed flexible mechanisms of peptide-polyketide chain off-loading via different intramolecular nucleophiles.
  • Demonstrated novel structural innovations in the biosynthesis of largimycins.

Abstract

-minus mutants suggests that a hydrolytic dehalogenation step proceeds before the peptide-polyketide chain is off-loaded from the polyketide synthase LrgJ. Remarkably, some compounds generated by these mutants bear a C-3 side chain that is cyclized into a unique β-thiolactone ring, a structural feature not seen before in natural products. Furthermore, this work has revealed alternative ways of peptide-polyketide chain off-loading by macrocyclization, unveiling the unprecedented flexibility of the thioesterase domain of LrgJ for selecting different intramolecular nucleophiles.

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Cite This Study

Becerril et al. (2026) studied this question.

synapsesocial.com/papers/69fed140b9154b0b828787ddhttps://doi.org/10.1021/acs.jnatprod.6c00240
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