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

Abstract

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.

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

“…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].…”

“…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]. In addition to the active site, the dimmer interface region defines a putative binding site known as the interface or misleadingly, allosteric site.…”

The Chemotherapy of Chagas Disease: An Overview

“…In addition, a unique trypanothione-dependent enzyme cascade neutralizes FAD and the disulfide bridge as intermediates. Two proton relays, one at each site, modulate the transfer [113,114]. discussion on the different aspects of inhibitors of specific enzymes acting as trypanocidals, in particular the possible use of drug leads [3,[125][126][127][128][129][130][131].…”