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

TitleEngineering of a Peptide α-N-Methyltransferase to Methylate Non-Proteinogenic Amino Acids.
Publication TypeJournal Article
Year of Publication2021
AuthorsSong, H, Burton, AJ, Shirran, SL, Fahrig-Kamarauskaitė, J, Kaspar, H, Muir, TW, Künzler, M, Naismith, JH
JournalAngew Chem Int Ed Engl
Volume60
Issue26
Pagination14319-14323
Date Published2021 06 21
ISSN1521-3773
KeywordsAmides, Amino Acids, Methylation, Methyltransferases, Peptides, Protein Conformation, Protein Engineering
Abstract

<p>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.</p>

DOI10.1002/anie.202100818
Alternate JournalAngew Chem Int Ed Engl
PubMed ID33856715
PubMed Central IDPMC8251615
Grant ListBB/R018189/1 / BB_ / Biotechnology and Biological Sciences Research Council / United Kingdom