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A QM/MM-based computational investigation on the catalytic mechanism of saccharopine reductase.

ABSTRACT: Saccharopine reductase from Magnaporthe grisea, an NADPH-containing enzyme in the ?-aminoadipate pathway, catalyses the formation of saccharopine, a precursor to L-lysine, from the substrates glutamate and ?-aminoadipate-?-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, ?-aminoadipate-?-semialdehyde and NADPH in a manner and polar environment conducive to reaction.

SUBMITTER: Almasi JN

PROVIDER: S-EPMC6264447 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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A QM/MM-based computational investigation on the catalytic mechanism of saccharopine reductase.

Almasi Joel N JN Bushnell Eric A C EA Gauld James W JW

Molecules (Basel, Switzerland) 20111012 10

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 en ...[more]

PMID: 21993247

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Project description:Human arginase I (HARGI) is a metalloprotein highly expressed in the liver cytosol and catalyzes the hydrolysis of l-arginine to form l-ornithine and urea. Understanding the reaction mechanism would be highly helpful to design new inhibitor molecules for HARGI as it is a target for heart- and blood-related diseases. In this study, we explored the hydrolysis reaction mechanism of HARGI with antiferromagnetic and ferromagnetic coupling between two Mn(II) ions at the catalytic site by employing molecular dynamics simulations coupled with quantum mechanics and molecular mechanics (QM/MM). The spin states, high-spin ferromagnetic couple (S Mn1 = 5/2, S Mn2 = 5/2), low-spin ferromagnetic couple (S Mn1 = 1/2, S Mn2 = 1/2), high-spin antiferromagnetic couple (S Mn1 = 5/2, S Mn2 = -5/2), and low-spin antiferromagnetic couple (S Mn1 = 1/2, S Mn2 = -1/2) are considered, and the calculated energetics for the complex of the substrate and HARGI are compared. The results show that the high-spin antiferromagnetic couple (S Mn1 = 5/2, S Mn2 = -5/2) is more stable than other spin states. The low-spin ferromagnetic and antiferromagnetic coupled states are highly unstable compared with the corresponding high-spin states. The high-spin antiferromagnetic couple (S Mn1 = 5/2, S Mn2 = -5/2) is stabilized by 0.39 kcal/mol compared with the ferromagnetic couple (S Mn1 = 5/2, S Mn2 = 5/2). The reaction mechanism is independent of spin states; however, the energetics of transition states and intermediates are more stable in the case of the high-spin antiferromagnetic couple (S Mn1 = 5/2, S Mn2 = -5/2) than the corresponding ferromagnetic state. It is evident that the calculated coupling constants are higher for antiferromagnetic states and, interestingly, superexchange coupling is found to occur between Mn(II) ions via hydroxide ions in a reactant. The hydroxide ion enhances the coupling interaction and initiates the catalytic reaction. It is also noted that the first intermediate structure where there is no superexchange coupling is similar to the known inhibitor 2(S)-amino-6-boronohexanoic acid.

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A QM/MM-based computational investigation on the catalytic mechanism of saccharopine reductase.

Publications

A QM/MM-based computational investigation on the catalytic mechanism of saccharopine reductase.

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