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A QM/MM–Based Computational Investigation on the Catalytic Mechanism of Saccharopine Reductase
Department of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario N9B 3P4, Canada
* Author to whom correspondence should be addressed.
Received: 5 September 2011; in revised form: 27 September 2011 / Accepted: 30 September 2011 / Published: 12 October 2011
Abstract: Saccharopine reductase from Magnaporthe grisea, an NADPH-containing enzyme in the α-aminoadipate pathway, catalyses the formation of saccharopine, a precursor to L-lysine, from the substrates glutamate and α-aminoadipate-δ-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, α-aminoadipate-δ-semialdehyde and NADPH in a manner and polar environment conducive to reaction.
Keywords: Schiff base; saccharopine reductase; α-aminoadipate-δ-semialdehyde; saccharopine; imine formation; carbinolamine; QM/MM; theoretical; computational
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Almasi, J.N.; Bushnell, E.A.; Gauld, J.W. A QM/MM–Based Computational Investigation on the Catalytic Mechanism of Saccharopine Reductase. Molecules 2011, 16, 8569-8589.
Almasi JN, Bushnell EA, Gauld JW. A QM/MM–Based Computational Investigation on the Catalytic Mechanism of Saccharopine Reductase. Molecules. 2011; 16(10):8569-8589.
Almasi, Joel N.; Bushnell, Eric A.C.; Gauld, James W. 2011. "A QM/MM–Based Computational Investigation on the Catalytic Mechanism of Saccharopine Reductase." Molecules 16, no. 10: 8569-8589.