QM/MM study on the catalytic mechanism of cyclohexane-1,2-dione hydrolase (CDH)

doi:10.1007/s00214-013-1442-9

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	QM/MM study on the catalytic mechanism of cyclohexane-1,2-dione hydrolase (CDH)
	Zhu, Wenyou 1; Liu, Yongjun 1,2; Liu, YJ (reprint author), Shandong Univ, Sch Chem & Chem Engn, Key Lab Colloid & Interface Chem, Minist Educ, Jinan 250100, Shandong, Peoples R China.
	2013-12-27
发表期刊	THEORETICAL CHEMISTRY ACCOUNTS
ISSN	1432-881X
卷号	133 期号:2
文章类型	Article
摘要	Cyclohexane-1,2-dione hydrolase (CDH) catalyzes the conversion of cyclohexane-1,2-dione (CDO) to 6-oxohexanoate. It is the first thiamine diphosphate (ThDP)-dependent enzyme that involves a C-C bond ring cleavage of alicyclic compound. In this paper, the detailed catalytic mechanism of CDH has been studied by using quantum mechanics/molecular mechanics approach. Since CDO exists in the form of monohydrated ketone in solution, and one of the two hydroxyl groups may exist in its neutral or deprotonated states, the substrate with different protonation states was firstly docked into the active site by using molecular docking. For the neutral form of CDO, only one binding mode (model A) was observed. In model A, the calculated catalytic reaction involves five elementary steps, and the cleavage of C1(CDO)-C2(ThDP) bond is the rate-limiting step with the energy barrier of 19.9 kcal/mol. For the deprotonated form of CDO, because any one of the two hydroxyl groups may be deprotonated, two binding modes can be found. But only one docking pose (model B) can lead to the conversion of CDO to 6-oxohexanoate, and the corresponding reaction contains three elementary steps, and two of which correspond to comparable energy barriers (15.2 vs 14.5 kcal/mol). Based on our comparison, it is concluded that the C-C bond cleavage is greatly facilitated by the deprotonation of CDO. From the energy point of view, both of the mechanisms derived from models A and B are possible for CDH catalytic reaction.; Cyclohexane-1,2-dione hydrolase (CDH) catalyzes the conversion of cyclohexane-1,2-dione (CDO) to 6-oxohexanoate. It is the first thiamine diphosphate (ThDP)-dependent enzyme that involves a C-C bond ring cleavage of alicyclic compound. In this paper, the detailed catalytic mechanism of CDH has been studied by using quantum mechanics/molecular mechanics approach. Since CDO exists in the form of monohydrated ketone in solution, and one of the two hydroxyl groups may exist in its neutral or deprotonated states, the substrate with different protonation states was firstly docked into the active site by using molecular docking. For the neutral form of CDO, only one binding mode (model A) was observed. In model A, the calculated catalytic reaction involves five elementary steps, and the cleavage of C1(CDO)-C2(ThDP) bond is the rate-limiting step with the energy barrier of 19.9 kcal/mol. For the deprotonated form of CDO, because any one of the two hydroxyl groups may be deprotonated, two binding modes can be found. But only one docking pose (model B) can lead to the conversion of CDO to 6-oxohexanoate, and the corresponding reaction contains three elementary steps, and two of which correspond to comparable energy barriers (15.2 vs 14.5 kcal/mol). Based on our comparison, it is concluded that the C-C bond cleavage is greatly facilitated by the deprotonation of CDO. From the energy point of view, both of the mechanisms derived from models A and B are possible for CDH catalytic reaction.
关键词	Cyclohexane-1 Reaction Mechanism 2-dione (Cdo) Cyclohexane-1 Qm/mm 2-dione Hydrolase (Cdh) Thiamine Diphosphate (Thdp)-dependent Enzyme
WOS标题词	Science & Technology ; Physical Sciences
DOI	10.1007/s00214-013-1442-9
关键词[WOS]	DIPHOSPHATE-DEPENDENT ENZYMES ; KETO-ENOL TRANSFORMATION ; THIAMIN DIPHOSPHATE ; CRYSTAL-STRUCTURE ; PK(A) VALUES ; PYRUVATE DECARBOXYLASE ; ANGSTROM RESOLUTION ; DENSITY ; RATIONALIZATION ; DYNAMICS
收录类别	SCI
语种	英语
项目资助者	Natural Science Foundation of China(21173129 ; 21373125)
WOS研究方向	Chemistry
WOS类目	Chemistry, Physical
WOS记录号	WOS:000329116300001
引用统计	被引频次：3[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	http://210.75.249.4/handle/363003/3886
专题	中国科学院西北高原生物研究所
通讯作者	Liu, YJ (reprint author), Shandong Univ, Sch Chem & Chem Engn, Key Lab Colloid & Interface Chem, Minist Educ, Jinan 250100, Shandong, Peoples R China.
作者单位	1.Shandong Univ, Sch Chem & Chem Engn, Key Lab Colloid & Interface Chem, Minist Educ, Jinan 250100, Shandong, Peoples R China 2.Chinese Acad Sci, Northwest Inst Plateau Biol, Xining 810001, Peoples R China
推荐引用方式 GB/T 7714	Zhu, Wenyou,Liu, Yongjun,Liu, YJ . QM/MM study on the catalytic mechanism of cyclohexane-1,2-dione hydrolase (CDH)[J]. THEORETICAL CHEMISTRY ACCOUNTS,2013,133(2).
APA	Zhu, Wenyou,Liu, Yongjun,&Liu, YJ .(2013).QM/MM study on the catalytic mechanism of cyclohexane-1,2-dione hydrolase (CDH).THEORETICAL CHEMISTRY ACCOUNTS,133(2).
MLA	Zhu, Wenyou,et al."QM/MM study on the catalytic mechanism of cyclohexane-1,2-dione hydrolase (CDH)".THEORETICAL CHEMISTRY ACCOUNTS 133.2(2013).

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