Structural Basis for the Prenylation Reaction of Carbazole‐Containing Natural Products Catalyzed by Squalene Synthase‐Like Enzymes
Structural Basis for the Prenylation Reaction of Carbazole‐Containing Natural Products Catalyzed by Squalene Synthase‐Like Enzymes
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类角鲨烯合酶催化含咔唑天然产物异戊二烯化反应的结构基础
DOI：
10.1002/anie.202117430
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Nagano Shingo
中科院分区：
文献类型：
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作者：
Nagata Ryuhei;Suemune Hironori;Kobayashi Masaya;Shinada Tetsuro;Shin‐ya Kazuo;Nishiyama Makoto;Hino Tomoya;Sato Yusuke;Kuzuyama Tomohisa;Nagano Shingo
一些酶被注释为角鲨烯合酶，催化细菌次级代谢中含咔唑-3，4-醌的底物的异戊烯化。它们的反应机制仍然不清楚，因为它们与充分表征的芳香族底物异戊二烯基转移酶（PT）的序列相似性低。我们确定的咔唑PT的晶体结构，这些显示，整体结构是很好地叠加在那些角鲨烯酶。相反，异戊二烯基供体和受体底物之间的堆叠相互作用类似于在芳香族底物PT中观察到的那些。结构和突变分析表明，Ile和Asp残基是必不可少的疏水性和亲水性相互作用的咔唑-3，4-醌部分的异戊二烯受体，分别，和一个中间σ-复合物涉及催化三联体的脱质子化机制提出。我们的研究结果提供了一个新的亚类芳香族底物PT的结构基础。
Some enzymes annotated as squalene synthase catalyze the prenylation of carbazole‐3,4‐quinone‐containing substrates in bacterial secondary metabolism. Their reaction mechanisms remain unclear because of their low sequence similarity to well‐characterized aromatic substrate prenyltransferases (PTs). We determined the crystal structures of the carbazole PTs, and these revealed that the overall structure is well superposed on those of squalene synthases. In contrast, the stacking interaction between the prenyl donor and acceptor substrates resembles those observed in aromatic substrate PTs. Structural and mutational analyses suggest that the Ile and Asp residues are essential for the hydrophobic and hydrophilic interactions with the carbazole‐3,4‐quinone moiety of the prenyl acceptor, respectively, and a deprotonation mechanism of an intermediary σ‐complex involving a catalytic triad is proposed. Our results provide a structural basis for a new subclass of aromatic substrate PTs.