Engineering Dehydro Amino Acids and Thioethers into Peptides Using Lacticin 481 Synthetase

Champak Chatterjee, Gregory C. Patton, Lisa Cooper, Moushumi Paul, Wilfred A. van der Donk

Research output: Contribution to journalArticle

Abstract

Lantibiotics are peptide antimicrobials containing the thioether-bridged amino acids lanthionine (Lan) and methyllanthionine (MeLan) and often the dehydrated residues dehydroalanine (Dha) and dehydrobutyrine (Dhb). While biologically advantageous, the incorporation of these residues into peptides is synthetically daunting, and their production in vivo is limited to peptides containing proteinogenic amino acids. The lacticin 481 synthetase LctM offers versatile control over the installation of dehydro amino acids and thioether rings into peptides. In vitro processing of semisynthetic substrates unrelated to the prelacticin 481 peptide demonstrated the broad substrate tolerance of LctM. Furthermore, a chemoenzymatic strategy was employed to generate novel thioether linkages by cyclization of peptidic substrates containing the nonproteinogenic cysteine analogs homocysteine and β-homocysteine. These findings are promising with respect to the utility of LctM toward preparation of conformationally constrained peptide therapeutics.

Original languageEnglish (US)
Pages (from-to)1109-1117
Number of pages9
JournalChemistry and Biology
Volume13
Issue number10
DOIs
StatePublished - Oct 1 2006

Keywords

  • CHEMBIO
  • MICROBIO

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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