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

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Song_2018_SciAdv_Nitrogenatoms_CC.pdf (2.619Mb)
Date
24/08/2018
Author
Song, Haigang
Van Der Velden, Niels S.
Shirran, Sally L.
Bleiziffer, Patrick
Zach, Christina
Sieber, Ramon
Imani, Aman S.
Krausbeck, Florian
Aebi, Markus
Freeman, Michael F.
Riniker, Sereina
Künzler, Markus
Naismith, James H.
Keywords
QH301 Biology
NDAS
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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.
Citation
Song , H , Van Der Velden , N S , Shirran , S L , Bleiziffer , P , Zach , C , Sieber , R , Imani , A S , Krausbeck , F , Aebi , M , Freeman , M F , Riniker , S , Künzler , M & Naismith , J H 2018 , ' A molecular mechanism for the enzymatic methylation of nitrogen atoms within peptide bonds ' , Science Advances , vol. 4 , no. 8 , eaat2720 . https://doi.org/10.1126/sciadv.aat2720
Publication
Science Advances
Status
Peer reviewed
DOI
https://doi.org/10.1126/sciadv.aat2720
ISSN
2375-2548
Type
Journal article
Rights
Copyright © 2018 The Authors. This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Description
This work was financially supported by ETH Zürich, University of Minnesota, the Swiss National Science Foundation (grant nos. 31003A_149512 and 200021–159713), Wellcome Trust (094476/Z/10/Z), ERC (NCB-TNT 339367), and BBSRC (BB/R018189/1).
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  • University of St Andrews Research
URI
http://hdl.handle.net/10023/15982

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