Mechanistic Studies on Dehydration in Class v Lanthipeptides

Haoqian Liang, Isaiah J. Lopez, Marina Sánchez-Hidalgo, Olga Genilloud, Wilfred A. Van Der Donk

Research output: Contribution to journalArticlepeer-review


Lanthipeptides are ribosomally synthesized and post-translationally modified peptides characterized by lanthionine (Lan) and/or methyllanthionine (MeLan) residues. Four classes of enzymes have been identified to install these structures in a substrate peptide. Recently, a novel class of lanthipeptides was discovered that lack genes for known class I-IV lanthionine synthases in their biosynthetic gene cluster (BGC). In this study, the dehydration of Ser/Thr during the biosynthesis of the class V lanthipeptide cacaoidin was reconstituted in vitro. The aminoglycoside phosphotransferase-like enzyme CaoK iteratively phosphorylates Ser/Thr residues on the precursor peptide CaoA, followed by phosphate elimination catalyzed by the HopA1 effector-like protein CaoY to achieve eight successive dehydrations. CaoY shows sequence similarity to the OspF family proteins and the lyase domains of class III/IV lanthionine synthetases, and mutagenesis studies identified residues that are critical for catalysis. An AlphaFold prediction of the structure of the dehydration enzyme complex engaged with its substrate suggests the importance of hydrophobic interactions between the CaoA leader peptide and CaoK in enzyme-substrate recognition. This model is supported by site-directed mutagenesis studies.

Original languageEnglish (US)
Pages (from-to)2519-2527
Number of pages9
JournalACS chemical biology
Issue number9
StatePublished - Sep 16 2022

ASJC Scopus subject areas

  • Molecular Medicine
  • Biochemistry


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