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

DOI: 10.1126/sciadv.aat2720 DOI Help

Authors: Haigang Song (University of St. Andrews; Wellcome Trust Centre of Human Genomics) , Niels S. Van Der Velden (Eidgenössische Technische Hochschule (ETH) Zürich) , Sally L. Shiran (University of St. Andrews) , Patrick Bleiziffer (Eidgenössische Technische Hochschule (ETH) Zürich) , Christina Zach (Eidgenössische Technische Hochschule (ETH) Zürich) , Ramon Sieber (Eidgenössische Technische Hochschule (ETH) Zürich) , Aman S. Imani (University of Minnesota–Twin Cities) , Florian Krausbeck (Eidgenössische Technische Hochschule (ETH) Zürich) , Markus Aebi (Eidgenössische Technische Hochschule (ETH) Zürich) , Michael F. Freeman (University of Minnesota–Twin Cities) , Sereina Riniker (Eidgenössische Technische Hochschule (ETH) Zürich) , Markus Künzler (Eidgenössische Technische Hochschule (ETH) Zürich) , James H. Naismith (Wellcome Trust Centre of Human Genomics; Sichuan University; Research Complex at Harwell)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Science Advances , VOL 4

State: Published (Approved)
Published: August 2018

Open Access Open Access

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.

Subject Areas: Biology and Bio-materials, Chemistry

Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I24-Microfocus Macromolecular Crystallography