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The amide bond with its planarity and lack of chemical reactivity is at the heart of protein structure. Chemical methylation of amides is known but was considered too harsh to be accessible to biology. Until last year there was no protein structure in the data bank with an enzymatically methylated amide. The discovery that the natural macrocyclic product, omphalotin is ribosomally synthesized, was not as had been assumed by non-ribosomal peptide synthesis. This was the first definitive evidence that an enzyme could methylate the amide bond. The enzyme, OphMA, iteratively self-hypermethylates its own C-terminus using SAM as cofactor. A second enzyme OphP, a prolyl oligopeptidase cleaves the core peptide from OphMA and cyclizes it into omphalotin. The molecular mechanism for OphMA was elucidated by mutagenesis, structural, biochemical and theoretical studies. This review highlights current progress in peptide N-methylating enzymes.

Original publication




Journal article


Current opinion in structural biology

Publication Date





79 - 88


Division of Structural Biology, Wellcome Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK; Research Complex at Harwell, Rutherford Laboratory, Didcot, Oxfordshire OX11 0FA, UK; The Rosalind Franklin Institute, Rutherford Laboratory, Didcot, Oxfordshire OX11 0FA, UK.


Amides, Peptides, Cyclic, Cyclosporine, Proteins, Protein Processing, Post-Translational, Methylation