Stuffed Methyltransferase Catalyzes the Penultimate Step of Pyochelin Biosynthesis

Trey A. Ronnebaum, Jeffrey S. McFarlane, Thomas E. Prisinzano, Squire J. Booker, Audrey L. Lamb

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


Nonribosomal peptide synthetases use tailoring domains to incorporate chemical diversity into the final natural product. A structurally unique set of tailoring domains are found to be stuffed within adenylation domains and have only recently begun to be characterized. PchF is the NRPS termination module in pyochelin biosynthesis and includes a stuffed methyltransferase domain responsible for S-adenosylmethionine (AdoMet)-dependent N-methylation. Recent studies of stuffed methyltransferase domains propose a model in which methylation occurs on amino acids after adenylation and thiolation rather than after condensation to the nascent peptide chain. Herein, we characterize the adenylation and stuffed methyltransferase didomain of PchF through the synthesis and use of substrate analogues, steady-state kinetics, and onium chalcogen effects. We provide evidence that methylation occurs through an SN2 reaction after thiolation, condensation, cyclization, and reduction of the module substrate cysteine and is the penultimate step in pyochelin biosynthesis.

Original languageEnglish (US)
Pages (from-to)665-678
Number of pages14
Issue number6
StatePublished - Feb 12 2019

All Science Journal Classification (ASJC) codes

  • Biochemistry


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