An S =1 Iron(IV) Intermediate Revealed in a Non‐Heme Iron Enzyme‐Catalyzed Oxidative C−S Bond Formation
An S =1 Iron(IV) Intermediate Revealed in a Non‐Heme Iron Enzyme‐Catalyzed Oxidative C−S Bond Formation
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非血红素铁酶催化氧化 C-S 键形成中揭示的 S =1 铁 (IV) 中间体
DOI：
10.1002/ange.202309362
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发表时间：
2023
影响因子：
--
通讯作者：
Chang, Wei‐chen
中科院分区：
文献类型：
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作者：
Paris, Jared C.;Hu, Sha;Wen, Aiwen;Weitz, Andrew C.;Cheng, Ronghai;Gee, Leland B.;Tang, Yijie;Kim, Hyomin;Vegas, Arturo;Chang, Wei‐chen
麦角硫因（ESH）和卵硫醇A（OSHA）是两种天然的硫醇-组氨酸衍生物。ESH被认为是一种长寿维生素，OSHA抑制肝癌的增殖。ESH和OSHA在需氧途径中的关键生物合成步骤是由非血红素铁酶催化的O2依赖性C-S键形成（例如，卵硫醇生物合成中的OvoA），但由于缺乏关键反应性中间体的鉴定，这种新反应的机制尚未解决。在这项研究中，我们报告了一个动力学上有竞争力的S =1铁（IV）中间体的鉴定和表征，该中间体由四个组氨酸配体环境（三个来自蛋白质残基，一个来自底物）支持，使来自Methylocytopenothermoleran的OvoA中的C-S键形成成为可能，这代表了第一个实验观察到的非血红素铁酶中的中间自旋铁（IV）物种。因此，本研究报告的结果为进一步剖析OSHA生物合成途径中酶促氧化C-S键形成的机制奠定了基础。它们还为研究富含组氨酸的配体环境支持的高价铁中间体的结构-功能关系提供了新的机会。
Ergothioneine (ESH) and ovothiol A (OSHA) are two natural thiol‐histidine derivatives. ESH has been implicated as a longevity vitamin and OSHA inhibits the proliferation of hepatocarcinoma. The key biosynthetic step of ESH and OSHA in the aerobic pathways is the O2‐dependent C−S bond formation catalyzed by non‐heme iron enzymes (e.g., OvoA in ovothiol biosynthesis), but due to the lack of identification of key reactive intermediate the mechanism of this novel reaction is unresolved. In this study, we report the identification and characterization of a kinetically competentS=1 iron(IV) intermediate supported by a four‐histidine ligand environment (three from the protein residues and one from the substrate) in enabling C−S bond formation in OvoA fromMethyloversatilis thermotoleran, which represents the first experimentally observed intermediate spin iron(IV) species in non‐heme iron enzymes. Results reported in this study thus set the stage to further dissect the mechanism of enzymatic oxidative C−S bond formation in the OSHA biosynthesis pathway. They also afford new opportunities to study the structure‐function relationship of high‐valent iron intermediates supported by a histidine rich ligand environment.