QM/MM studies on the catalytic mechanism of Phenylethanolamine N-methyltransferase

NWIPB OpenIR

	QM/MM studies on the catalytic mechanism of Phenylethanolamine N-methyltransferase
	Hou, Q. Q.1; Wang, J. H.1; Gao, J.1; Liu, Y. J.1,2; Liu, C. B.1
	2012-04-01
发表期刊	BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS
ISSN	1570-9639
卷号	1824 期号:4 页码:533-541
文章类型	Article
摘要	Epinephrine is a naturally occurring adrenomedullary hormone that transduces environmental stressors into cardiovascular actions. As the only route in the catecholamine biosynthetic pathway, Phenylethanolamine N-methyltransferase (PNMT) catalyzes the synthesis of epinephrine. To elucidate the detailed mechanism of enzymatic catalysis of PNMT, combined quantum-mechanical/molecular-mechanical (QM/MM) calculations were performed. The calculation results reveal that this catalysis contains three elementary steps: the deprotonation of protonated norepinphrine, the methyl transferring step and deprotonation of the methylated norepinphrine. The methyl transferring step was proved to be the rate-determining step undergoing a SN2 mechanism with an energy barrier of 16.4 kcal/mol. During the whole catalysis, two glutamic acids Glu185 and Glu219 were proved to be loaded with different effects according to the calculations results of the mutants. These calculation results can be used to explain the experimental observations and make a good complementarity for the previous QM study. (C) 2012 Elsevier B.V. All rights reserved.; Epinephrine is a naturally occurring adrenomedullary hormone that transduces environmental stressors into cardiovascular actions. As the only route in the catecholamine biosynthetic pathway, Phenylethanolamine N-methyltransferase (PNMT) catalyzes the synthesis of epinephrine. To elucidate the detailed mechanism of enzymatic catalysis of PNMT, combined quantum-mechanical/molecular-mechanical (QM/MM) calculations were performed. The calculation results reveal that this catalysis contains three elementary steps: the deprotonation of protonated norepinphrine, the methyl transferring step and deprotonation of the methylated norepinphrine. The methyl transferring step was proved to be the rate-determining step undergoing a SN2 mechanism with an energy barrier of 16.4 kcal/mol. During the whole catalysis, two glutamic acids Glu185 and Glu219 were proved to be loaded with different effects according to the calculations results of the mutants. These calculation results can be used to explain the experimental observations and make a good complementarity for the previous QM study. (C) 2012 Elsevier B.V. All rights reserved.
关键词	Qm/mm Epinephrine Methyltransferase Reaction Mechanism Mutation
WOS标题词	Science & Technology ; Life Sciences & Biomedicine
关键词[WOS]	MOLECULAR-DYNAMICS ; ENZYMATIC-REACTIONS ; PK(A) VALUES ; ADRENALINE ; INHIBITORS ; BRAIN ; BINDING ; SYSTEM ; PNMT ; RATIONALIZATION
收录类别	SCI
语种	英语
WOS研究方向	Biochemistry & Molecular Biology ; Biophysics
WOS类目	Biochemistry & Molecular Biology ; Biophysics
WOS记录号	WOS:000302443000001
引用统计	被引频次：9[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/363003/3696
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, Q. Q.,Wang, J. H.,Gao, J.,et al. QM/MM studies on the catalytic mechanism of Phenylethanolamine N-methyltransferase[J]. BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS,2012,1824(4):533-541.
APA	Hou, Q. Q.,Wang, J. H.,Gao, J.,Liu, Y. J.,&Liu, C. B..(2012).QM/MM studies on the catalytic mechanism of Phenylethanolamine N-methyltransferase.BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS,1824(4),533-541.
MLA	Hou, Q. Q.,et al."QM/MM studies on the catalytic mechanism of Phenylethanolamine N-methyltransferase".BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS 1824.4(2012):533-541.

条目包含的文件		下载所有文件
文件名称/大小	文献类型	版本类型	开放类型	使用许可
QMMM studies on the （1428KB）			开放获取	--	浏览下载