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Structural Insights into the CotB2-Catalyzed Cyclization of Geranylgeranyl Diphosphate to the Diterpene Cyclooctat-9-en-7-ol
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2017-05-02 00:00:00 , DOI: 10.1021/acschembio.7b00154 Takeo Tomita , Seung-Young Kim , Kazuya Teramoto , Ayuko Meguro , Taro Ozaki , Ayako Yoshida , Yudai Motoyoshi , Naoki Mori , Ken Ishigami , Hidenori Watanabe , Makoto Nishiyama 1 , Tomohisa Kuzuyama
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2017-05-02 00:00:00 , DOI: 10.1021/acschembio.7b00154 Takeo Tomita , Seung-Young Kim , Kazuya Teramoto , Ayuko Meguro , Taro Ozaki , Ayako Yoshida , Yudai Motoyoshi , Naoki Mori , Ken Ishigami , Hidenori Watanabe , Makoto Nishiyama 1 , Tomohisa Kuzuyama
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The diterpene cyclase CotB2 catalyzes the cyclization of geranylgeranyl diphosphate (GGPP) to the tricyclic cyclooctat-9-en-7-ol, which is characterized by a 5-8-5-fused ring skeleton. We have previously proposed a cyclization cascade involving a unique carbon–carbon bond rearrangement combined with multiple hydride shifts, all occurring at a single active site. Here, we report the first high-resolution X-ray crystal structure of CotB2 with bound substrate analog geranylgeranyl thiodiphosphate (GGSPP). In the GGSPP-bound form, GGSPP folds into a unique S-shaped conformation that probably reflects the substrate-bound state prior to ionization of the substrate GGPP. The folded framework of GGSPP is surrounded by hydrophobic residues and several aromatic and asparagine residues that are well-positioned to stabilize a series of reactive carbocation intermediates through a combination of cation−π and dipole charge interactions. The combined crystal structures and mutagenesis-based biochemical assays provide a structural basis for exquisite control of ring formation and stereochemistry during CotB2 catalysis.
中文翻译：
结构观察到的CotB2催化的Geranylgeranyl Diphosphate到二萜Cyclooctat-9-en-7-ol的环化反应
二萜环化酶CotB2催化香叶基香叶基二磷酸香叶酯（GGPP）环化为三环环辛酯9-en-7-ol，其特征是5-8-5稠合的环骨架。我们之前曾提出过一个环化级联反应，该反应涉及独特的碳-碳键重排结合多个氢化物转移，所有这些转移都发生在单个活性位点上。在这里，我们报告与绑定的基板类似物香叶基香叶基硫代二磷酸（GGSPP）的CotB2的第一个高分辨率X射线晶体结构。在与GGSPP结合的形式中，GGSPP折叠成独特的S形构象，该构象可能反映了底物GGPP电离之前与底物结合的状态。GGSPP的折叠框架被疏水残基和几个芳香族和天冬酰胺残基所包围，这些残基位置合适，可通过阳离子-π和偶极电荷相互作用的组合来稳定一系列反应性碳正离子中间体。结合的晶体结构和基于诱变的生化分析为CotB2催化过程中环形成和立体化学的精确控制提供了结构基础。
更新日期：2017-05-02
中文翻译：
结构观察到的CotB2催化的Geranylgeranyl Diphosphate到二萜Cyclooctat-9-en-7-ol的环化反应
二萜环化酶CotB2催化香叶基香叶基二磷酸香叶酯（GGPP）环化为三环环辛酯9-en-7-ol，其特征是5-8-5稠合的环骨架。我们之前曾提出过一个环化级联反应，该反应涉及独特的碳-碳键重排结合多个氢化物转移，所有这些转移都发生在单个活性位点上。在这里，我们报告与绑定的基板类似物香叶基香叶基硫代二磷酸（GGSPP）的CotB2的第一个高分辨率X射线晶体结构。在与GGSPP结合的形式中，GGSPP折叠成独特的S形构象，该构象可能反映了底物GGPP电离之前与底物结合的状态。GGSPP的折叠框架被疏水残基和几个芳香族和天冬酰胺残基所包围，这些残基位置合适，可通过阳离子-π和偶极电荷相互作用的组合来稳定一系列反应性碳正离子中间体。结合的晶体结构和基于诱变的生化分析为CotB2催化过程中环形成和立体化学的精确控制提供了结构基础。
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