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

7 Citations (Scopus)
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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
Number of pages6
JournalAngewandte Chemie International Edition
VolumeEarly View
Early online date15 Apr 2021
DOIs
Publication statusE-pub ahead of print - 15 Apr 2021

Keywords

  • Cyclic peptide
  • RiPPs
  • α-N-methylation
  • Non-proteinogenic amino acids
  • Split intein

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