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Molecules 2011, 16(10), 8569-8589; doi:10.3390/molecules16108569
Article

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

,  and *
Received: 5 September 2011; in revised form: 27 September 2011 / Accepted: 30 September 2011 / Published: 12 October 2011
(This article belongs to the Special Issue Enzyme-Catalyzed Reactions)
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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 Schiff base; saccharopine reductase; α-aminoadipate-δ-semialdehyde; saccharopine; imine formation; carbinolamine; QM/MM; theoretical; computational
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

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.

AMA Style

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.

Chicago/Turabian Style

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.


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