Distributive and directional behavior of lantibiotic synthetases revealed by high-resolution tandem mass spectrometry

M. Violet Lee, Leigh Anne Furgerson Ihnken, Ok You Young, Amanda L. McClerren, Wilfred A. Van Der Donk, Neil L. Kelleher

Research output: Contribution to journalArticlepeer-review

48 Scopus citations


The lantibiotic synthetases LctM and HalM2 are bifunctional enzymes that catalyze both the dehydration of serine and threonine residues and the Michael-type additions of cysteine residues to the resulting dehydroamino acids in their substrate peptides. Using Fourier transform mass spectrometry to analyze these activities in vitro, the dehydration is shown to take place by a distributive mechanism, with build-up of intermediates observed in electrospray mass spectra. The cyclization activity of HalM2 was monitored through alkylation of free cysteines in intermediates, providing access to the regioselectivity of lanthionine ring formation using high-resolution tandem mass spectrometry. HalM2 is shown to catalyze the cyclization process in a largely N- to C-terminal directional fashion, forming a total of four lanthionine rings in its HalA2 substrate. These studies advance a model for lantibiotic production where substrate binding via an N-terminal leader results in dehydration and cyclization on similar time scales and with a high, though not strict, propensity for N-to-C directionality.

Original languageEnglish (US)
Pages (from-to)12258-12264
Number of pages7
JournalJournal of the American Chemical Society
Issue number34
StatePublished - Sep 2 2009

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry
  • Catalysis
  • Colloid and Surface Chemistry


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