Substrate control in stereoselective lanthionine biosynthesis

Weixin Tang, Gonzalo Jiménez-Osés, K. N. Houk, Wilfred A. Van Der Donk

Research output: Contribution to journalArticlepeer-review

Abstract

Enzymes are typically highly stereoselective catalysts that enforce a reactive conformation on their native substrates. We report here a rare example in which the substrate controls the stereoselectivity of an enzyme-catalysed Michael-type addition during the biosynthesis of lanthipeptides. These natural products contain thioether crosslinks formed by a cysteine attack on dehydrated Ser and Thr residues. We demonstrate that several lanthionine synthetases catalyse highly selective anti-additions in which the substrate (and not the enzyme) determines whether the addition occurs from the re or si face. A single point mutation in the peptide substrate completely inverted the stereochemical outcome of the enzymatic modification. Quantum mechanical calculations reproduced the experimentally observed selectivity and suggest that conformational restraints imposed by the amino-acid sequence on the transition states determine the face selectivity of the Michael-type cyclization.

Original languageEnglish (US)
Pages (from-to)57-64
Number of pages8
JournalNature Chemistry
Volume7
Issue number1
DOIs
StatePublished - Jan 1 2015

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)

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