Insights into the biosynthesis of duramycin

Liujie Huo, Ayşe Ökesli, Ming Zhao, Wilfred A. van der Donk*

*Corresponding author for this work

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Lantibiotics are ribosomally synthesized and posttranslationally modified antimicrobial peptides that are characterized by the thioether cross-linked bisamino acids lanthionine (Lan) and methyllanthionine (MeLan). Duramycin contains 19 amino acids, including one Lan and two MeLans, an unusual lysinoalanine (Lal) bridge formed from the ε-amino group of lysine 19 and a serine residue at position 6, and an erythro-3-hydroxy-L-aspartic acid at position 15. These modifications are important for the interactions of duramycin with its biological target, phosphatidylethanolamine (PE). Based on the binding affinity and specificity for PE, duramycin has been investigated as a potential therapeutic, as a molecular probe to investigate the role and localization of PE in biological systems, and to block viral entry into mammalian cells. In this study, we identified the duramycin biosynthetic gene cluster by genome sequencing of Streptomyces cinnamoneus ATCC 12686 and investigated the dur biosynthetic machinery by heterologous expression in Escherichia coli. In addition, the analog duramycin C, containing six amino acid changes compared to duramycin, was successfully generated in E. coli. The substrate recognition motif of DurX, an α-ketoglutarate/iron(II)-dependent hydroxylase that carries out the hydroxylation of aspartate 15 of the precursor peptide DurA, was also investigated using mutagenesis of the DurA peptide. Both in vivo and in vitro results demonstrated that Gly16 is important for DurX activity.

Original languageEnglish (US)
Article numbere02698-16
JournalApplied and Environmental Microbiology
Volume83
Issue number3
DOIs
StatePublished - 2017

Keywords

  • Antibiotic
  • Antiviral agents
  • Biosynthesis
  • Duramycin
  • Phosphatidylethanolamine

ASJC Scopus subject areas

  • Biotechnology
  • Food Science
  • Applied Microbiology and Biotechnology
  • Ecology

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