Transition structure and reactive complexes for hydride transfer in an isoalloxazine-nicotinamide complex. On the catalytic mechanism of glutathione reductase. An ab initio MO SCF study

Díaz, Wladimiro; Aullo, J.M.; Paulino, Margot; Tapia, O.

doi:10.1016/0301-0104(95)00425-4

Cited by 9 publications

(7 citation statements)

References 41 publications

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“…The structural catalytic elements in GR and TR are conserved, namely, the redox active isoalloxazine ring of FAD, the disulfide bridge, and two couples of proton relay residues at the G-site and N-site. The proton relay function acts during the electron transfer step [23,24]. The electrons from the nicotinamide are thought to flow successively along the isoalloxazine and the disulfide bridge, finally reducing the substrate disulfide [23,24].…”

Section: Introductionmentioning

confidence: 99%

Assaying phenothiazine derivatives as trypanothione reductase and glutathione reductase inhibitors by theoretical docking and Molecular Dynamics studies

Iribarne¹,

Paulino²,

Aguilera³

et al. 2009

Journal of Molecular Graphics and Modelling

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Section: Introductionmentioning

confidence: 99%

Assaying phenothiazine derivatives as trypanothione reductase and glutathione reductase inhibitors by theoretical docking and Molecular Dynamics studies

Iribarne¹,

Paulino²,

Aguilera³

et al. 2009

Journal of Molecular Graphics and Modelling

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“…The redox head of NADPH is represented by 1,4-dihydro-3-amide pyridine (the nicotinamide residue). The geometry of the TS calculated by Diaz et al [6] was used to seed the calculations.…”

Section: Modelmentioning

confidence: 99%

“…The ping-pong case corresponds to two redox steps separated in time and space as mentioned previously. For the SO mechanism, it is required that an enzyme±NADP + complex is formed ®rst, followed by subsequent production of the tertiary complex: substrate-enzyme±NADP + [3,6].…”

Section: Systemmentioning

confidence: 99%

“…The two electrons and one proton are then located somehow at the FAD-SS and the proton relay system. From a theoretical viewpoint, besides the TS for HT by Diaz et al [6], very little is known about these mechanisms. The fate of the proton at the N-site is equally important in both mechanisms.…”

Section: Introductionmentioning

confidence: 99%

“…A quantum chemical transition structure (TS) was determined by Diaz et al [6] using the isoalloxazine/nicotinamide molecular model. As this (TS) can be accommodated at the active site of GR without steric hindrances, these authors suggested that the SO mechanism could be related to the HT mechanism, an idea backed by previous experimental evidence [1,7].…”

Section: Introductionmentioning

confidence: 99%

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Hydride-transfer transition structure as a possible unifying redox step for decscribing the branched mechanism of glutathione reductase. Molecular-electronic antecedents

Iribarne

Paulino

Tapia

2000

Theoretical Chemistry Accounts: Theory, Computation, and Modeli

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For glutathione reductase (GR), a mammalian reduced nicotinamide adenine dinucleotide phosphate dependent¯avoenzyme participating in free-radical detoxi®cation pathways, we present a quantum chemical study addressing aspects of its electronic mechanism. The system is known to sustain both ping-pong and sequentially ordered mechanisms depending upon particular conditions. Isoalloxazine and nicotinamide-N-protonated rings are taken as a minimum model. The AM1 method and the AMSOL program are used throughout. Starting from a transition-state structure, docked at GRs active site, and successively including molecular elements of the active site relevant to the redox processes, geometry-optimized binary and tertiary complexes are characterized suggesting a plausible description for the sequentially ordered mechanism. The ping-pong mechanism relates to an electron-transfer (ET) mechanism. An ET binary complex between nicotinamide and the isoalloxazine ring was characterized. Its electronic structure is controlled by the protonation state of the proton relay found at this active site. The excess proton in the relay comes from the previous hydride-transfer step. The experimental stereoselectivity is then ful®lled. The state of charge (standard Mulliken population analysis) shows an excess of two electrons on the isoalloxazine ring and almost one on the nicotinamide ring. The overall results suggest that both mechanisms can be controlled by the same hydridetransfer structure, the dierence between them being determined by changes in the oxidized coenzyme binding strength to the protein and/or the strength of the protein±substrate interactions.

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Probing the hydride transfer process in the lumiflavine–1-methylnicotinamide model system using group softness

et al. 2004

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Transition structure and reactive complexes for hydride transfer in an isoalloxazine-nicotinamide complex. On the catalytic mechanism of glutathione reductase. An ab initio MO SCF study

Cited by 9 publications

References 41 publications

Assaying phenothiazine derivatives as trypanothione reductase and glutathione reductase inhibitors by theoretical docking and Molecular Dynamics studies

Assaying phenothiazine derivatives as trypanothione reductase and glutathione reductase inhibitors by theoretical docking and Molecular Dynamics studies

Hydride-transfer transition structure as a possible unifying redox step for decscribing the branched mechanism of glutathione reductase. Molecular-electronic antecedents

Probing the hydride transfer process in the lumiflavine–1-methylnicotinamide model system using group softness

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