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<p>Non-ribosomal peptide synthetases (NRPSs) produce diverse bioactive peptides, including antibiotics and antitumour agents, by integrating proteinogenic and non-proteinogenic amino acids alongside tailoring modifications, such as epimerization (E) and cyclization. Here we demonstrate that the tetrahydropyrimidine ring of pyoverdine is synthesized by the condensation (C) domain PvdL-C<sub>3</sub>, revealing cyclization capability of a canonical NRPS domain. Analyses of PvdL-E<sub>2</sub>C<sub>3</sub>A<sub>3</sub> cross-module structures reveal a stable E-C didomain catalytic platform maintained by the donor communication-mediating domain. Through mutagenesis and evolutionary analyses, we identified key active site residues shaping the catalytic channel, controlling both efficiency and specificity. We further engineered PvdL-C<sub>3</sub> to accept <span>l</span>-epimers, unveiling latent substrate flexibility. Ultimately, our work provides a unifying model where domain architecture and catalytic channel features collectively govern NRPS function, elucidating a cyclization mechanism and providing a structural blueprint for future enzyme engineering.</p><p></p>

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Analysis of heterocycle formation and stereochemical control by a non-ribosomal peptide synthetase condensation domain

  • 期刊论文

  • 发表日期：

    2026年3月23日

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  • Wei Cao,
  • Jialiang Wang,
  • Shyue Leh Chen,
  • Dandan Li,
  • Xiaozheng Wang,
  • Zixin Deng,
  • Jingdan Liang,
  • Zhijun Wang

摘要

Non-ribosomal peptide synthetases (NRPSs) produce diverse bioactive peptides, including antibiotics and antitumour agents, by integrating proteinogenic and non-proteinogenic amino acids alongside tailoring modifications, such as epimerization (E) and cyclization. Here we demonstrate that the tetrahydropyrimidine ring of pyoverdine is synthesized by the condensation (C) domain PvdL-C3, revealing cyclization capability of a canonical NRPS domain. Analyses of PvdL-E2C3A3 cross-module structures reveal a stable E-C didomain catalytic platform maintained by the donor communication-mediating domain. Through mutagenesis and evolutionary analyses, we identified key active site residues shaping the catalytic channel, controlling both efficiency and specificity. We further engineered PvdL-C3 to accept l-epimers, unveiling latent substrate flexibility. Ultimately, our work provides a unifying model where domain architecture and catalytic channel features collectively govern NRPS function, elucidating a cyclization mechanism and providing a structural blueprint for future enzyme engineering.