期刊
SCIENCE ADVANCES
卷 4, 期 8, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.aat2720
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资金
- ETH Zurich
- University of Minnesota
- Swiss National Science Foundation [31003A_149512, 200021-159713]
- Wellcome Trust [094476/Z/10/Z]
- ERC [NCB-TNT 339367]
- BBSRC [BB/R018189/1]
- BBSRC [BB/R018189/1] Funding Source: UKRI
- Wellcome Trust [094476/Z/10/Z] Funding Source: Wellcome Trust
- Swiss National Science Foundation (SNF) [31003A_149512, 200021_159713] Funding Source: Swiss National Science Foundation (SNF)
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 catenanelike 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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