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首页> 外文期刊>The FEBS journal >Crystal structure of a ring-cleaving cyclohexane-1,2-dione hydrolase, a novel member of the thiamine diphosphate enzyme family
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Crystal structure of a ring-cleaving cyclohexane-1,2-dione hydrolase, a novel member of the thiamine diphosphate enzyme family

机译：环己烷-1,2-二酮水解酶（硫胺素二磷酸酶家族的新成员）的晶体结构

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摘要

The thiamine diphosphate (ThDP) dependent flavoenzyme cyclohexane-1,2-dione hydrolase (CDH) catalyses a key step of a novel anaerobic degradation pathway for alicyclic alcohols by converting cyclohexane-1,2-dione (CDO) to 6-oxohexanoate and further to adipate using NAD+ as electron acceptor. To gain insights into the molecular basis of these reactions CDH from denitrifying anaerobe Azoarcus sp. strain 22Lin was structurally characterized at 1.26 angstrom resolution. Notably, the active site funnel is rearranged in an unprecedented manner providing the structural basis for the specific binding and cleavage of an alicyclic compound. Crucial features include a decreased and displaced funnel entrance, a semi-circularly shaped loop segment preceding the C-terminal arm and the attachment of the C-terminal arm to other subunits of the CDH tetramer. Its structural scaffold and the ThDP activation is related to that observed for other members of the ThDP enzyme family. The selective binding of the competitive inhibitor 2-methyl-2,4-pentane-diol (MPD) to the open funnel of CDH reveals an asymmetry of the two active sites found also in the dimer of several other ThDP dependent enzymes. The substrate binding site is characterized by polar and non-polar moieties reflected in the structures of MPD and CDO and by three prominent histidine residues (His28, His31 and His76) that most probably play a crucial role in substrate activation. The NAD+ dependent oxidation of 6-oxohexanoate remains enigmatic as the redox-active cofactor FAD seems not to participate in catalysis, and no obvious NAD+ binding site is found. Based on the structural data both reactions are discussed.
机译：硫胺素二磷酸（ThDP）依赖性黄酮酶环己烷-1,2-二酮水解酶（CDH）催化脂环族醇的新型厌氧降解途径的关键步骤，该方法通过将环己烷-1,2-二酮（CDO）转化为6-氧代己酸酯而进一步使用NAD +作为电子受体进行己二酸为了深入了解这些反应的分子基础，CDH来自反硝化厌氧菌Azoarcus sp。菌株22Lin的结构特征为1.26埃分辨率。值得注意的是，活性位点漏斗以前所未有的方式重新排列，为脂环化合物的特异性结合和裂解提供了结构基础。重要特征包括漏斗入口减少和移位，C末端臂之前的半圆形环段以及C末端臂与CDH四聚体的其他亚基的连接。其结构支架和ThDP激活与ThDP酶家族其他成员所观察到的有关。竞争性抑制剂2-甲基-2,4-戊烷二醇（MPD）与CDH的开放漏斗的选择性结合揭示了在其他几种ThDP依赖性酶的二聚体中也发现的两个活性位点的不对称性。底物结合位点的特征是在MPD和CDO结构中反映的极性和非极性部分，以及三个最可能在底物激活中起关键作用的组氨酸残基（His28，His31和His76）。 NAD +依赖的6-氧代己酸酯的氧化仍然是不可思议的，因为氧化还原活性辅因子FAD似乎不参与催化，并且没有发现明显的NAD +结合位点。基于结构数据，讨论了两种反应。

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