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The Catalytic Mechanism of the Class C Radical S ‐Adenosylmethionine Methyltransferase NosN
Author(s) -
Ding Wei,
Li Yongzhen,
Zhao Junfeng,
Ji Xinjian,
Mo Tianlu,
Qianzhu Haocheng,
Tu Tao,
Deng Zixin,
Yu Yi,
Chen Fener,
Zhang Qi
Publication year - 2017
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201609948
Subject(s) - sn2 reaction , methyltransferase , methylation , chemistry , nucleophile , stereochemistry , biosynthesis , enzyme , catalysis , mechanism (biology) , biochemistry , dna , philosophy , epistemology
S ‐Adenosylmethionine (SAM) is one of the most common co‐substrates in enzyme‐catalyzed methylation reactions. Most SAM‐dependent reactions proceed through an S N 2 mechanism, whereas a subset of them involves radical intermediates for methylating non‐nucleophilic substrates. Herein, we report the characterization and mechanistic investigation of NosN, a class C radical SAM methyltransferase involved in the biosynthesis of the thiopeptide antibiotic nosiheptide. We show that, in contrast to all known SAM‐dependent methyltransferases, NosN does not produce S ‐adenosylhomocysteine (SAH) as a co‐product. Instead, NosN converts SAM into 5′‐methylthioadenosine as a direct methyl donor, employing a radical‐based mechanism for methylation and releasing 5′‐thioadenosine as a co‐product. A series of biochemical and computational studies allowed us to propose a comprehensive mechanism for NosN catalysis, which represents a new paradigm for enzyme‐catalyzed methylation reactions.