Investigation of the substrate specificity of lacticin 481 synthetase by using nonproteinogenic amino acids

Matthew R. Levengood, Christopher C. Kerwood, Champak Chatterjee, Wilfred A. van der Donk

Research output: Contribution to journalArticlepeer-review


Lantibiotics are peptide antimicrobial compounds that are characterized by the thioether-bridged amino acids lanthionine and methyllanthionine. For lacticin 481, these structures are installed in a two-step post-translational modification process by a bifunctional enzyme, lacticin 481 synthetase (LctM). LctM catalyzes the dehydration of Ser and Thr residues to generate dehydroalanine or dehydrobutyrine, respectively, and the subsequent intramolecular regio- and stereospecific Michael-type addition of cysteines onto the dehydroamino acids. In this study, semisynthetic substrates containing nonproteinogenic amino acids were prepared by expressed protein ligation and [3+2]-cycloaddition of azide and alkyne-functionalized peptides. LctM demonstrated broad substrate specificity toward substrates containing β-amino acids, D-amino acids, and N-alkyl amino acids (peptoids) in certain regions of its peptide substrate. These findings showcase its promise for use in lantibiotic and peptide-engineering applications, whereby nonproteinogenic amino acids might impart improved stability or modulated biological activities. Furthermore, LctM permitted the incorporation of an alkyne-containing amino acid that can be utilized for the site-selective modification of mature lantibiotics and used in target identification.

Original languageEnglish (US)
Pages (from-to)911-919
Number of pages9
Issue number5
StatePublished - Mar 23 2009


  • Antibiotics
  • Biosynthesis
  • Lantibiotics
  • Peptides
  • Peptoids
  • Post-translational modifications

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Organic Chemistry


Dive into the research topics of 'Investigation of the substrate specificity of lacticin 481 synthetase by using nonproteinogenic amino acids'. Together they form a unique fingerprint.

Cite this