Engineering of a Peptide α-N-Methyltransferase to Methylate Non-Proteinogenic Amino Acids

Haigang Song, Antony J. Burton, Sally L. Shirran, Jūratė Fahrig-Kamarauskaitė, Hannelore Kaspar, Tom W. Muir, Markus Künzler, James H. Naismith

Research output: Contribution to journalArticlepeer-review

Abstract

Introduction of α-N-methylated non-proteinogenic amino acids into peptides can improve their biological activities, membrane permeability and proteolytic stability. This is commonly achieved, in nature and in the lab, by assembling pre-methylated amino acids. The more appealing route of methylating amide bonds is challenging. Biology has evolved an α-N-automethylating enzyme, OphMA, which acts on the amide bonds of peptides fused to its C-terminus. Due to the ribosomal biosynthesis of its substrate, the activity of this enzyme towards peptides with non-proteinogenic amino acids has not been addressed. An engineered OphMA, intein-mediated protein ligation and solid-phase peptide synthesis have allowed us to demonstrate the methylation of amide bonds in the context of non-natural amides. This approach may have application in the biotechnological production of therapeutic peptides.

Original languageEnglish (US)
JournalAngewandte Chemie - International Edition
DOIs
StateAccepted/In press - 2021

All Science Journal Classification (ASJC) codes

  • Catalysis
  • Chemistry(all)

Keywords

  • cyclic peptide
  • non-proteinogenic amino acids
  • RiPPs
  • split intein
  • α-N-methylation

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