A QM/MM-Based Computational Investigation on the Catalytic Mechanism of Saccharopine Reductase

被引:7
作者
Almasi, Joel N. [1 ]
Bushnell, Eric A. C. [1 ]
Gauld, James W. [1 ]
机构
[1] Univ Windsor, Dept Chem & Biochem, Windsor, ON N9B 3P4, Canada
基金
加拿大自然科学与工程研究理事会;
关键词
Schiff base; saccharopine reductase; alpha-aminoadipate-delta-semialdehyde; saccharopine; imine formation; carbinolamine; QM/MM; theoretical; computational; ALPHA-AMINOADIPATE PATHWAY; SCHIFF-BASE; GEOMETRY OPTIMIZATION; LYSINE BIOSYNTHESIS; MAGNAPORTHE-GRISEA; IMINE FORMATION; ONIOM; APPROXIMATIONS; KINETICS; SYSTEMS;
D O I
10.3390/molecules16108569
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Saccharopine reductase from Magnaporthe grisea, an NADPH-containing enzyme in the alpha-aminoadipate pathway, catalyses the formation of saccharopine, a precursor to L-lysine, from the substrates glutamate and alpha-aminoadipate-delta-semialdehyde. Its catalytic mechanism has been investigated using quantum mechanics/molecular mechanics (QM/MM) ONIOM-based approaches. In particular, the overall catalytic pathway has been elucidated and the effects of electron correlation and the anisotropic polar protein environment have been examined via the use of the ONIOM(HF/6-31G(d): AMBER94) and ONIOM(MP2/6-31G(d)//HF/6-31G(d): AMBER94) methods within the mechanical embedding formulism and ONIOM(MP2/6-31G(d)//HF/6-31G(d):AMBER94) and ONIOM(MP2/6-311G(d, p)//HF/6-31G(d): AMBER94) within the electronic embedding formulism. The results of the present study suggest that saccharopine reductase utilises a substrate-assisted catalytic pathway in which acid/base groups within the cosubstrates themselves facilitate the mechanistically required proton transfers. Thus, the enzyme appears to act most likely by binding the three required reactant molecules glutamate, alpha-aminoadipate-delta-semialdehyde and NADPH in a manner and polar environment conducive to reaction.
引用
收藏
页码:8569 / 8589
页数:21
相关论文
共 35 条
[1]  
Bearpark MJ, 2007, AIP CONF PROC, V2, P583, DOI 10.1063/1.2836147
[2]   KINETICS AND MECHANISM OF HYDROLYSIS OF 2,2,2-TRIFLUORO-N-(3-METHYL-2-CYCLOHEXENYLIDENE)ETHYLAMINE - ALPHA, BETA-UNSATURATED SCHIFF-BASE [J].
BRAULT, M ;
POLLACK, RM ;
BEVINS, CL .
JOURNAL OF ORGANIC CHEMISTRY, 1976, 41 (02) :346-350
[3]   The Amber biomolecular simulation programs [J].
Case, DA ;
Cheatham, TE ;
Darden, T ;
Gohlke, H ;
Luo, R ;
Merz, KM ;
Onufriev, A ;
Simmerling, C ;
Wang, B ;
Woods, RJ .
JOURNAL OF COMPUTATIONAL CHEMISTRY, 2005, 26 (16) :1668-1688
[4]   A new ONIOM implementation in Gaussian98.: Part I.: The calculation of energies, gradients, vibrational frequencies and electric field derivatives [J].
Dapprich, S ;
Komáromi, I ;
Byun, KS ;
Morokuma, K ;
Frisch, MJ .
JOURNAL OF MOLECULAR STRUCTURE-THEOCHEM, 1999, 461 :1-21
[5]   Computational studies on Schiff-base formation: Implications for the catalytic mechanism of porphobilinogen synthase [J].
Erdtman, Edvin ;
Bushnell, Eric A. C. ;
Gauld, James W. ;
Eriksson, Leif A. .
COMPUTATIONAL AND THEORETICAL CHEMISTRY, 2011, 963 (2-3) :479-489
[6]  
Frisch M, 2015, Gaussian 09, revision a 02
[7]   Structure-stability correlations for imine formation in aqueous solution [J].
Godoy-Alcántar, C ;
Yatsimirsky, AK ;
Lehn, JM .
JOURNAL OF PHYSICAL ORGANIC CHEMISTRY, 2005, 18 (10) :979-985
[8]   High-level ab initio molecular orbital calculations of imine formation [J].
Hall, NE ;
Smith, BJ .
JOURNAL OF PHYSICAL CHEMISTRY A, 1998, 102 (25) :4930-4938
[9]   Quantum chemical modeling of enzyme active sites and reaction mechanisms [J].
Himo, Fahmi .
THEORETICAL CHEMISTRY ACCOUNTS, 2006, 116 (1-3) :232-240
[10]   The IMOMO method: Integration of different levels of molecular orbital approximations for geometry optimization of large systems: Test for n-butane conformation and S(N)2 reaction: RCl+Cl- [J].
Humbel, S ;
Sieber, S ;
Morokuma, K .
JOURNAL OF CHEMICAL PHYSICS, 1996, 105 (05) :1959-1967