Format

Send to

Choose Destination
Sci Adv. 2018 Aug 24;4(8):eaat2720. doi: 10.1126/sciadv.aat2720. eCollection 2018 Aug.

A molecular mechanism for the enzymatic methylation of nitrogen atoms within peptide bonds.

Author information

1
Biomedical Sciences Research Complex, North Haugh, University of St. Andrews, Fife KY16 9ST, UK.
2
Division of Structural Biology, Wellcome Trust Centre of Human Genomics, Roosevelt Drive, Oxford OX3 7BN, UK.
3
Institute of Microbiology, Department of Biology, Eidgenössische Technische Hochschule (ETH) Zürich, Zürich, Switzerland.
4
Laboratory of Physical Chemistry, Department of Chemistry and Applied Biosciences, Eidgenössische Technische Hochschule (ETH) Zürich, Zürich, Switzerland.
5
Department of Biochemistry, Molecular Biology, and Biophysics, and BioTechnology Institute, University of Minnesota-Twin Cities, St. Paul, MN 55108, USA.
6
State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China.
7
Research Complex at Harwell, Rutherford Laboratory, Didcot, Oxfordshire OX11 0FA, UK.

Abstract

The peptide bond, the defining feature of proteins, governs peptide chemistry by abolishing nucleophilicity of the nitrogen. This and the planarity of the peptide bond arise from the delocalization of the lone pair of electrons on the nitrogen atom into the adjacent carbonyl. While chemical methylation of an amide bond uses a strong base to generate the imidate, OphA, the precursor protein of the fungal peptide macrocycle omphalotin A, self-hypermethylates amides at pH 7 using S-adenosyl methionine (SAM) as cofactor. The structure of OphA reveals a complex catenane-like arrangement in which the peptide substrate is clamped with its amide nitrogen aligned for nucleophilic attack on the methyl group of SAM. Biochemical data and computational modeling suggest a base-catalyzed reaction with the protein stabilizing the reaction intermediate. Backbone N-methylation of peptides enhances their protease resistance and membrane permeability, a property that holds promise for applications to medicinal chemistry.

Supplemental Content

Full text links

Icon for PubMed Central
Loading ...
Support Center