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Crystal structure of a ring-cleaving cyclohexane-1,2-dione hydrolase, a novel member of the thiamine diphosphate enzyme family

Crystal structure of a ring-cleaving cyclohexane-1,2-dione hydrolase, a novel member of the thiamine diphosphate enzyme family

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STEINBACH, Alma, Sonja FRAAS, Jens HARDER, Eberhard WARKENTIN, Peter KRONECK, Ulrich ERMLER, 2012. Crystal structure of a ring-cleaving cyclohexane-1,2-dione hydrolase, a novel member of the thiamine diphosphate enzyme family. In: FEBS Journal. 279(7), pp. 1209-1219. ISSN 1742-464X. eISSN 1742-4658

@article{Steinbach2012-04Cryst-23574, title={Crystal structure of a ring-cleaving cyclohexane-1,2-dione hydrolase, a novel member of the thiamine diphosphate enzyme family}, year={2012}, doi={10.1111/j.1742-4658.2012.08513.x}, number={7}, volume={279}, issn={1742-464X}, journal={FEBS Journal}, pages={1209--1219}, author={Steinbach, Alma and Fraas, Sonja and Harder, Jens and Warkentin, Eberhard and Kroneck, Peter and Ermler, Ulrich} }

2013-06-11T14:35:19Z Steinbach, Alma deposit-license Ermler, Ulrich FEBS Journal ; 279 (2012), 7. - S. 1209-1219 Warkentin, Eberhard Kroneck, Peter The thiamine diphosphate (ThDP) dependent flavoenzyme cyclohexane-1,2-dione hydrolase (CDH) (EC 3.7.1.11) 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<sup>+</sup> 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 Å 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<sup>+</sup> dependent oxidation of 6-oxohexanoate remains enigmatic as the redox-active cofactor FAD seems not to participate in catalysis, and no obvious NAD<sup>+</sup> binding site is found. Based on the structural data both reactions are discussed. Ermler, Ulrich Kroneck, Peter Fraas, Sonja Harder, Jens 2012-04 Fraas, Sonja 2013-06-11T14:35:19Z Warkentin, Eberhard Steinbach, Alma Harder, Jens Crystal structure of a ring-cleaving cyclohexane-1,2-dione hydrolase, a novel member of the thiamine diphosphate enzyme family eng

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