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Engineering of a Peptide α‐N‐Methyltransferase to Methylate Non‐Proteinogenic Amino Acids
Author(s) -
Song Haigang,
Burton Antony J.,
Shirran Sally L.,
FahrigKamarauskaitė Jūratė,
Kaspar Hannelore,
Muir Tom W.,
Künzler Markus,
Naismith James H.
Publication year - 2021
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.202100818
Subject(s) - amino acid , peptide bond , chemistry , peptide , chemical ligation , methylation , peptide synthesis , biochemistry , stereochemistry , amide , biosynthesis , intein , enzyme , rna , rna splicing , gene
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.