2025-09-12 理化学研究所
NATの触媒するSAM変換反応
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ノカルディシン生合成における3-アミノ-3-カルボキシプロピル転移の構造基盤 Structural Basis for 3-Amino-3-carboxypropyl Transfer in Nocardicin Biosynthesis
Yaojie Gao,Masayuki Karasawa,Zhiyang Quan,Takahiro Mori,Masahiro Kanaida,Craig A. Townsend,Tohru Terada,Ikuro Abe,and Takayoshi Awakawa
Journal of the American Chemical Society Published: September 8, 2025
DOI:https://doi.org/10.1021/jacs.5c08367
Abstract
S-Adenosyl-l-methionine (SAM) is well-known as a methyl donor for methyltransferases but also functions as a 3-amino-3-carboxypropyl (3-ACP) donor for 3-ACP transferases. NAT is a 3-ACP transferase which accepts β-lactam antibiotic nocardicin G (1) and SAM to produce isonocardicin C. Due to the lack of structural information about this enzyme, its reaction mechanism has not been fully identified. In this study, we report two X-ray crystal structures of NAT, including its apo and complex structure with 1 and SAH. Examination of them identified the structural basis for substrate recognition. Comprehensive approach integrating site-directed mutagenesis, thermal shift assay, MD simulation, and QM/MM calculation revealed that the Cα-amino group of SAM functions as a Brønsted base to enhance the nucleophilicity of the C6′-OH of 1, with the assistance of E143, thereby facilitating SN2 attack on the Cγ of SAM. This study presents structural and computational analysis leading to more precise understanding of 3-ACP transfer.
