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A QM/MM study of the catalytic mechanism of nicotinamidase
Sheng, Xiang1; Liu, Yongjun1,2
2014
Source PublicationORGANIC & BIOMOLECULAR CHEMISTRY
ISSN1477-0520
Volume12Issue:8Pages:1265-1277
SubtypeArticle
AbstractNicotinamidase (Pnc1) is a member of Zn-dependent amidohydrolases that hydrolyzes nicotinamide (NAM) to nicotinic acid (NA), which is a key step in the salvage pathway of NAD(+) biosynthesis. In this paper, the catalytic mechanism of Pnc1 has been investigated by using a combined quantum-mechanical/molecular-mechanical (QM/MM) approach based on the recently obtained crystal structure of Pnc1. The reaction pathway, the detail of each elementary step, the energetics of the whole catalytic cycle, and the roles of key residues and Zn-binding site are illuminated. Our calculation results indicate that the catalytic water molecule comes from the bulk solvent, which is then deprotonated by residue D8. D8 functions as a proton transfer station between C167 and NAM, while the activated C167 serves as the nucleophile. The residue K122 only plays a role in stabilizing intermediates and transition states. The oxyanion hole formed by the amide backbone nitrogen atoms of A163 and C167 has the function to stabilize the hydroxyl anion of nicotinamide. The Zn-binding site rather than a single Zn2+ ion acts as a Lewis acid to influence the reaction. Two elementary steps, the activation of C167 in the deamination process and the decomposition of catalytic water in the hydrolysis process, correspond to the large energy barriers of 25.7 and 28.1 kcal mol(-1), respectively, meaning that both of them contribute a lot to the overall reaction barrier. Our results may provide useful information for the design of novel and efficient Pnc1 inhibitors and related biocatalytic applications.; Nicotinamidase (Pnc1) is a member of Zn-dependent amidohydrolases that hydrolyzes nicotinamide (NAM) to nicotinic acid (NA), which is a key step in the salvage pathway of NAD(+) biosynthesis. In this paper, the catalytic mechanism of Pnc1 has been investigated by using a combined quantum-mechanical/molecular-mechanical (QM/MM) approach based on the recently obtained crystal structure of Pnc1. The reaction pathway, the detail of each elementary step, the energetics of the whole catalytic cycle, and the roles of key residues and Zn-binding site are illuminated. Our calculation results indicate that the catalytic water molecule comes from the bulk solvent, which is then deprotonated by residue D8. D8 functions as a proton transfer station between C167 and NAM, while the activated C167 serves as the nucleophile. The residue K122 only plays a role in stabilizing intermediates and transition states. The oxyanion hole formed by the amide backbone nitrogen atoms of A163 and C167 has the function to stabilize the hydroxyl anion of nicotinamide. The Zn-binding site rather than a single Zn2+ ion acts as a Lewis acid to influence the reaction. Two elementary steps, the activation of C167 in the deamination process and the decomposition of catalytic water in the hydrolysis process, correspond to the large energy barriers of 25.7 and 28.1 kcal mol(-1), respectively, meaning that both of them contribute a lot to the overall reaction barrier. Our results may provide useful information for the design of novel and efficient Pnc1 inhibitors and related biocatalytic applications.
WOS HeadingsScience & Technology ; Physical Sciences
WOS KeywordMOLECULAR-DYNAMICS SIMULATIONS ; MYCOBACTERIUM-TUBERCULOSIS ; SACCHAROMYCES-CEREVISIAE ; ADENINE-DINUCLEOTIDE ; ENZYMATIC-REACTIONS ; CRYSTAL-STRUCTURE ; TRANSITION-STATE ; METAL-IONS ; PYRAZINAMIDASE ; INHIBITION
Indexed BySCI
Language英语
WOS Research AreaChemistry
WOS SubjectChemistry, Organic
WOS IDWOS:000330792500013
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Cited Times:11[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://210.75.249.4/handle/363003/4285
Collection中国科学院西北高原生物研究所
Affiliation1.Shandong Univ, Sch Chem & Chem Engn, Jinan 250100, Shandong, Peoples R China
2.Chinese Acad Sci, Northwest Inst Plateau Biol, Xining 810001, Qinghai, Peoples R China
Recommended Citation
GB/T 7714
Sheng, Xiang,Liu, Yongjun. A QM/MM study of the catalytic mechanism of nicotinamidase[J]. ORGANIC & BIOMOLECULAR CHEMISTRY,2014,12(8):1265-1277.
APA Sheng, Xiang,&Liu, Yongjun.(2014).A QM/MM study of the catalytic mechanism of nicotinamidase.ORGANIC & BIOMOLECULAR CHEMISTRY,12(8),1265-1277.
MLA Sheng, Xiang,et al."A QM/MM study of the catalytic mechanism of nicotinamidase".ORGANIC & BIOMOLECULAR CHEMISTRY 12.8(2014):1265-1277.
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