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

Science Advances
Haigang SongJames H Naismith

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.

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Citations

Jan 5, 2019·Organic & Biomolecular Chemistry·Hsiao-Ching LinYit-Heng Chooi
Apr 21, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Shangwen Luo, Shi-Hui Dong
May 31, 2019·Applied Microbiology and Biotechnology·Eva Vogt, Markus Künzler
Sep 17, 2020·Natural Product Reports·Manuel Montalbán-LópezWilfred A van der Donk
Dec 6, 2019·Chembiochem : a European Journal of Chemical Biology·Richard DemmlerDirk Hoffmeister
Jul 13, 2020·Current Opinion in Structural Biology·Haigang Song, James H Naismith
Feb 9, 2021·Current Opinion in Biotechnology·Chunyu Wu, Wilfred A van der Donk
Jun 12, 2020·Toxicon : Official Journal of the International Society on Toxinology·E E Robles-GómezE Antúnez-Argüelles
Apr 16, 2021·Angewandte Chemie·Haigang SongJames H Naismith
Aug 17, 2021·Journal of the American Chemical Society·Alexander A VinogradovHiroaki Suga
Jun 4, 2020·ACS Chemical Biology·Haigang SongMarkus Künzler
Oct 2, 2019·The Journal of Physical Chemistry. B·Bella L GrigorenkoAlexander V Nemukhin
May 24, 2019·Journal of the American Chemical Society·Marissa R QuijanoMichael F Freeman
Sep 4, 2021·Nature Chemical Biology·Jesko Koehnke
Sep 4, 2021·Nature Chemical Biology·Inseok SongSeokhee Kim
Sep 11, 2021·Nature Communications·Fredarla S MillerMichael F Freeman
Sep 29, 2021·Natural Product Reports·Simon C Kessler, Yit-Heng Chooi

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Methods Mentioned

BETA
neutron diffraction
size-exclusion chromatography
gel filtration

Software Mentioned

MaxEnt
Mascot
SCIEX PeakView
Thermo Fisher Xcalibur
GROMOS
PeakView
xia2
autoPROC
COOT
Phaser

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