State Key Laboratory of High-Efficiency Utilization of Coal and Green Chemical Engineering, School of Chemistry and Chemical Engineering, Ningxia University, Yinchuan, 750021, China.
State Key Laboratory of Physical Chemistry of Solid Surfaces and Fujian Provincial Key Laboratory of Theoretical and Computational Chemistry, College of Chemistry and Chemical Engineering, Innovation Laboratory for Sciences and Technologies of Energy Materials of Fujian Province (IKKEM), Xiamen University, Xiamen, 361005, China.
Angew Chem Int Ed Engl. 2022 Dec 12;61(50):e202214235. doi: 10.1002/anie.202214235. Epub 2022 Nov 15.
The non-heme iron ergothioneine synthase (EgtB) is a sulfoxide synthase that catalyzes oxidative C-S bond formation in the synthesis of ergothioneine, which plays roles against oxidative stress in cells. Despite extensive experimental and computational studies of the catalytic mechanisms of EgtB, the root causes for the selective C-S bond formation remain elusive. Using quantum mechanics/molecular mechanics (QM/MM) calculations, we show herein that a coordination switch of the sulfoxide intermediate is involved in the catalysis of the non-heme iron EgtB. This coordination switch from the S to the O atom is driven by the S/π electrostatic interactions, which efficiently promotes the observed stereoselective C-S bond formation while bypassing cysteine dioxygenation. The present mechanism is in agreement with all available experimental data, including regioselectivity, stereoselectivity and KIE results. This match underscores the critical role of coordination switching in the catalysis of non-heme enzymes.
非血红素铁埃格特烯合酶（EgtB）是一种亚砜合酶，可在埃格特烯的合成中催化氧化 C-S 键形成，该酶在细胞中发挥抗氧化应激作用。尽管对 EgtB 的催化机制进行了广泛的实验和计算研究，但选择性 C-S 键形成的根本原因仍难以捉摸。本文使用量子力学/分子力学（QM/MM）计算表明，亚砜中间体的配位开关参与了非血红素铁 EgtB 的催化。这种从 S 到 O 原子的配位开关是由 S/π 静电相互作用驱动的，这有效地促进了观察到的立体选择性 C-S 键形成，同时绕过半胱氨酸双加氧酶。该机制与所有可用的实验数据一致，包括区域选择性、立体选择性和 KIE 结果。这种匹配突出了配位开关在非血红素酶催化中的关键作用。
