Non-modular fatty acid synthases yield distinct N-terminal acylation in ribosomal peptides

Hengqian Ren, Chunshuai Huang, Yuwei Pan, Shravan R. Dommaraju, Haiyang Cui, Maolin Li, Mayuresh G. Gadgil, Douglas A. Mitchell, Huimin Zhao

Research output: Contribution to journalArticlepeer-review


Recent efforts in genome mining of ribosomally synthesized and post-translationally modified peptides (RiPPs) have expanded the diversity of post-translational modification chemistries. However, RiPPs are rarely reported as hybrid molecules incorporating biosynthetic machinery from other natural product families. Here we report lipoavitides, a class of RiPP/fatty-acid hybrid lipopeptides that display a unique, putatively membrane-targeting 4-hydroxy-2,4-dimethylpentanoyl (HMP)-modified N terminus. The HMP is formed via condensation of isobutyryl-coenzyme A (isobutyryl-CoA) and methylmalonyl-CoA catalysed by a 3-ketoacyl-(acyl carrier protein) synthase III enzyme, followed by successive tailoring reactions in the fatty acid biosynthetic pathway. The HMP and RiPP substructures are then connected by an acyltransferase exhibiting promiscuous activity towards the fatty acyl and RiPP substrates. Overall, the discovery of lipoavitides contributes a prototype of RiPP/fatty-acid hybrids and provides possible enzymatic tools for lipopeptide bioengineering. (Figure presented.).

Original languageEnglish (US)
JournalNature Chemistry
StateAccepted/In press - 2024

ASJC Scopus subject areas

  • General Chemistry
  • General Chemical Engineering


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