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

NWIPB OpenIR

	A QM/MM study on the catalytic mechanism of pyruvate decarboxylase
	Hou, Qianqian ; Gao, Jun ; Liu, Yongjun ; Liu, Chengbu
	2012-10-01
发表期刊	THEORETICAL CHEMISTRY ACCOUNTS ; Wang, WY; Ma, YG; Xu, J; Wang, HC; Zhu, JF; Zhou, HK.A QM/MM study on the catalytic mechanism of pyruvate decarboxylase,THEORETICAL CHEMISTRY ACCOUNTS,2012,131(10):
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.
文献类型	期刊论文
条目标识符	http://210.75.249.4/handle/363003/36848
专题	中国科学院西北高原生物研究所
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, Wang, WY; Ma, YG; Xu, J; Wang, HC; Zhu, JF; Zhou, HK.A QM/MM study on the catalytic mechanism of pyruvate decarboxylase,THEORETICAL CHEMISTRY ACCOUNTS,2012,131(10):,2012.
APA	Hou, Qianqian,Gao, Jun,Liu, Yongjun,&Liu, Chengbu.(2012).A QM/MM study on the catalytic mechanism of pyruvate decarboxylase.THEORETICAL CHEMISTRY ACCOUNTS.
MLA	Hou, Qianqian,et al."A QM/MM study on the catalytic mechanism of pyruvate decarboxylase".THEORETICAL CHEMISTRY ACCOUNTS (2012).