A QM/MM study on the catalytic mechanism of pyruvate decarboxylase

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	A QM/MM study on the catalytic mechanism of pyruvate decarboxylase
	Hou, Qianqian 1; Gao, Jun 1; Liu, Yongjun 1,2; Liu, Chengbu 1
	2012-10-01
发表期刊	THEORETICAL CHEMISTRY ACCOUNTS
ISSN	1432-881X
卷号	131 期号:10
文章类型	Article
摘要	Pyruvate decarboxylase (PDC) is a typical thiamin diphosphate (ThDP)-dependent enzyme with widespread applications in industry. Though studies regarding the reaction mechanism of PDC have been reported, they are mainly focused on the formation of ThDP ylide and some elementary steps in the catalytic cycle, studies about the whole catalytic cycle of PDC are still not completed. In these previous studies, a major controversy is whether the key active residues (Glu473, Glu50', Asp27', His113', His114') are protonated or ionized during the reaction. To explore the catalytic mechanism and the role of key residues in the active site, three whole-enzyme models were considered, and the combined QM/MM calculations on the nonoxidative decarboxylation of pyruvate to acetaldehyde catalyzed by PDC were performed. According to our computational results, the fundamental reaction pathways, the complete energy profiles of the whole catalytic cycle, and the specific role of key residues in the common steps were obtained. It is also found that the same residue with different protonation states will lead to different reaction pathways and energy profiles. The mechanism derived from the model in which the residues (Glu473, Glu50', Asp27', His113', His114') are in their protonated states is most consistent with experimental observations. Therefore, extreme care must be taken when assigning the protonation states in the mechanism study. Because the experimental determination of protonation state is currently difficult, the combined QM/MM method provides an indirect means for determining the active-site protonation state.; Pyruvate decarboxylase (PDC) is a typical thiamin diphosphate (ThDP)-dependent enzyme with widespread applications in industry. Though studies regarding the reaction mechanism of PDC have been reported, they are mainly focused on the formation of ThDP ylide and some elementary steps in the catalytic cycle, studies about the whole catalytic cycle of PDC are still not completed. In these previous studies, a major controversy is whether the key active residues (Glu473, Glu50', Asp27', His113', His114') are protonated or ionized during the reaction. To explore the catalytic mechanism and the role of key residues in the active site, three whole-enzyme models were considered, and the combined QM/MM calculations on the nonoxidative decarboxylation of pyruvate to acetaldehyde catalyzed by PDC were performed. According to our computational results, the fundamental reaction pathways, the complete energy profiles of the whole catalytic cycle, and the specific role of key residues in the common steps were obtained. It is also found that the same residue with different protonation states will lead to different reaction pathways and energy profiles. The mechanism derived from the model in which the residues (Glu473, Glu50', Asp27', His113', His114') are in their protonated states is most consistent with experimental observations. Therefore, extreme care must be taken when assigning the protonation states in the mechanism study. Because the experimental determination of protonation state is currently difficult, the combined QM/MM method provides an indirect means for determining the active-site protonation state.
关键词	Pyruvate Decarboxylase Decarboxylation Protonation State Combined Qm/mm Reaction Mechanism
WOS标题词	Science & Technology ; Physical Sciences
关键词[WOS]	SITE-DIRECTED MUTAGENESIS ; ZYMOMONAS-MOBILIS ; MOLECULAR-DYNAMICS ; CRYSTAL-STRUCTURE ; ANGSTROM RESOLUTION ; DEPENDENT ENZYMES ; TRANSITION-STATE ; PK(A) VALUES ; DIPHOSPHATE ; RATIONALIZATION
收录类别	SCI
语种	英语
WOS研究方向	Chemistry
WOS类目	Chemistry, Physical
WOS记录号	WOS:000309862600006
引用统计	被引频次：13[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/363003/3602
专题	中国科学院西北高原生物研究所
作者单位	1.Shandong Univ, Sch Chem & Chem Engn, Minist Educ, Key Lab Colloid & Interface Chem, Jinan 250100, Shandong, Peoples R China 2.Chinese Acad Sci, NW Inst Plateau Biol, Key Lab Adaptat & Evolut Plateau Biota, Xining 810001, Qinghai, Peoples R China
推荐引用方式 GB/T 7714	Hou, Qianqian,Gao, Jun,Liu, Yongjun,et al. A QM/MM study on the catalytic mechanism of pyruvate decarboxylase[J]. THEORETICAL CHEMISTRY ACCOUNTS,2012,131(10).
APA	Hou, Qianqian,Gao, Jun,Liu, Yongjun,&Liu, Chengbu.(2012).A QM/MM study on the catalytic mechanism of pyruvate decarboxylase.THEORETICAL CHEMISTRY ACCOUNTS,131(10).
MLA	Hou, Qianqian,et al."A QM/MM study on the catalytic mechanism of pyruvate decarboxylase".THEORETICAL CHEMISTRY ACCOUNTS 131.10(2012).

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