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<p>The macrocyclic scaffolds of non-ribosomal peptides (NRPs) are typically constructed by thioesterase (TE) domains, α/β-hydrolase fold enzymes located at the C-termini of non-ribosomal peptide synthetases (NRPSs). By employing various nucleophiles, TEs serve as sources of diversity in cyclization modes and ring-closing linkages of NRPs. The NRPS assembly line of momomycin, an unusual undecapeptidyl cyclic peptide with multiple backbone <i>N</i>-methylations, suggests that it is macrocyclized via the coupling of homochiral termini through a secondary amine nucleophile, which is rarely employed in TE-mediated cyclization. Here, we investigated the function of the momomycin cyclase, MmmB-TE. In vitro enzymatic assays revealed MmmB-TE’s strict specificity for an <span>l</span>-configured cyclic amine nucleophile, as well as the incremental enhancements of cyclization efficiency conferred by backbone <i>N</i>-methylations. Mutagenesis studies, together with computational modeling of the peptide-<i>O</i>-enzyme complex, provided insights into the binding of the ring-closing residues in MmmB-TE.</p>

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An atypical non-ribosomal peptide cyclase catalyzing homochiral coupling with cyclic amine nucleophile

  • 期刊论文

  • 发表日期：

    2025年12月17日

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  • Mitsuo Aono,
  • Yuito Yamada,
  • Kenichi Matsuda,
  • Toshiyuki Wakimoto

摘要

The macrocyclic scaffolds of non-ribosomal peptides (NRPs) are typically constructed by thioesterase (TE) domains, α/β-hydrolase fold enzymes located at the C-termini of non-ribosomal peptide synthetases (NRPSs). By employing various nucleophiles, TEs serve as sources of diversity in cyclization modes and ring-closing linkages of NRPs. The NRPS assembly line of momomycin, an unusual undecapeptidyl cyclic peptide with multiple backbone N-methylations, suggests that it is macrocyclized via the coupling of homochiral termini through a secondary amine nucleophile, which is rarely employed in TE-mediated cyclization. Here, we investigated the function of the momomycin cyclase, MmmB-TE. In vitro enzymatic assays revealed MmmB-TE’s strict specificity for an l-configured cyclic amine nucleophile, as well as the incremental enhancements of cyclization efficiency conferred by backbone N-methylations. Mutagenesis studies, together with computational modeling of the peptide-O-enzyme complex, provided insights into the binding of the ring-closing residues in MmmB-TE.