The Molecular Basis of the Antioxidant Capability of Glutathione Unraveled via Aerosol VUV Photoelectron Spectroscopy (original) (raw)
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Antioxidant Potential of Glutathione: A Theoretical Study
The Journal of Physical Chemistry B, 2011
All possible XÀH (where X can be C, N, O or S) bond dissociation energies (BDEs) of glutathione (γ-L-glutamyl-L-cysteinyl-glycine, GSH) and its fragments have been calculated by first principle methods, and the antioxidant potential of GSH was revealed to be higher than expected in earlier studies. Electron delocalization was found to have an important influence on the antioxidant potential. All structures were optimized and their harmonic vibrational frequencies were calculated in the gas phase at the B3LYP/6-31G(d) level of theory. Solvent effects were taken into account for optimizations at the same level of theory by applying the conductor-like polarizable continuum model (CPCM). Hydrogen cleavage from glutathione proved that the G3MP2B3 composite method provides results consistent with the experimental values for bond dissociation enthalpies (DH 298 ) of SÀH, OÀH, CÀH, and NÀH bonds. In order to replace the G3MP2B3 energies with accurate single point calculations, six density functionals, namely, MPWKCIS, MPWKCIS1K, M06, TPSS1KCIS, TPSSh, and B3LYP, were tested against G3MP2B3 for obtaining accurate bond dissociation energies. The MPWKCIS1K/6-311++G(3df,2p)//B3LYP/6-31G(d) level of theory provides the best correlation with the G3MP2B3 method for BDEs in both phases, and therefore, it is recommended for similar calculations. Gas phase results showed that the OÀH bond was the weakest, while in aqueous phase the NÀH bond in the ammonium group proved to have the smallest BDE value in the studied system. In both cases, the cleavage of the XÀH bond was followed by decarboxylation which was responsible for the energetic preference of these processes over the SÀH dissociation, which was regarded as the most favorable one until now. The calculated BDE values showed that in aqueous phase the most preferred H-abstraction site is at the weakest NÀH bond (BDE aq = 349.3 kJ mol À1 ) in the glutamine fragment near the α-carbon. In water, the formation of N-centered radicals compared to S-centered ones (BDE aq = 351.7 kJ mol À1 ) is more endothermic by 2.54 kJ mol À1 , due to decarboxylation. Hydrogen dissociation energies from the α-carbons are also comparable in energy with those of the thiol hydrogen, within computational error. The higher stability of the radicals;except the S-centered ones;is due to various degrees of electron delocalization. In aqueous phase, four quasi-equivalent stable radical centers (the α-carbons, the N-centered radical of the NH 2 group, and the S-centered radical) were found which provide the antioxidant behavior of glutathione.
ChemPlusChem, 2013
A gas‐phase radical rearrangement through intramolecular hydrogen‐atom transfer (HAT) was studied in the glutathione radical cation, [γ‐ECG]+., which was generated by a homolytic cleavage of the protonated S‐nitrosoglutathione. Ion–molecule reactions suggested that the radical migrates from the original sulfur position to one of the α‐carbon atoms. Experiments on the radical cations of dipeptides derived from the glutathione sequence, [γ‐EC]+. and [CG]+., pointed to the glutamic acid α‐carbon atom as the most likely site of the radical migration. Infrared multiple‐photon dissociation (IRMPD) spectroscopy was employed to generate complementary information. IRMPD of [γ‐ECG]+. in the approximately 1000–1800 cm−1 region was inconclusive owing to the relatively broad, overlapping absorption bands. However, the IRMPD spectrum of [γ‐EC]+. in this region was consistent with the radical migrating from the sulfur to the α‐carbon atom of glutamic acid. IRMPD in the 2800–3700 cm−1 region perfor...
A spectrophotometric study of the VO 2+ -glutathione interactions
Biological Trace Element Research, 1991
The interaction of the vanadyl (IV) cation with reduced glutathione (GSH) has been investigated by electronic absorption spectroscopy, at different metal-to-ligand ratios and pH values. The interaction depends strongly on the initial VO2+/GSH ratio. Starting with a tenfold GSH excess, coordination takes place through the two carboxylate groups of the ligand, generating (at pH=7) a blue 1∶2 VO2+/GSH complex; this stoichiometry could be confirmed by photometric titration experiments. Higher GSH concentrations produce a violet complex, which can also be obtained by addition of GSH to the blue species. Some measurements with the three component amino acids of GSH, as well as results obtained from the VO 3−/GSH system, allowed a wider insight into the characteristics of this violet complex, in which the cation interacts with S and N atoms of the peptide.
The system VO2++oxidized glutathione: a potentiometric and spectroscopic study
Journal of Inorganic Biochemistry, 2001
The equilibria in the system VO 1oxidized glutathione in aqueous solution have been studied in the pH range 2-11 by a combination of pH potentiometry and spectroscopy EPR, visible absorption and circular dichroism). The results of the various methods are self-consistent and the equilibrium model includes the species MLH , MLH , MLH , MLH, ML, MLH , MLH and several hydrolysis 4 3 2 21 22 products (where H L denotes oxidized glutathione); individual formation constants and spectra are given. Plausible structures for each 4 stoichiometry are discussed.
Structure–function relationships in glutathione and its analogues
Org. Biomol. Chem., 2003
The results are presented of measurements of protonation constants (potentiometry and NMR), UV spectroscopic properties and redox potentials of GSH and its five analogues, which are modified at the C-terminal glycine residue (γGlu-Cys-X, X = Gly, Gly-NH 2 , Gly-OEt, Ala, Glu, Ser). Strong linear correlations were found between various properties of the thiol and other functions of these peptides. These results allow discussion of the relationships between the structures and properties in glutathione and its analogues, and provide a novel chemical background for the issue of control of GSH reactivity.
Glutathione – Hydroxyl Radical Interaction: A Theoretical Study on Radical Recognition Process
PLoS ONE, 2013
Non-reactive, comparative (261.2 ms) molecular dynamics simulations were carried out to characterize the interactions between glutathione (GSH, host molecule) and hydroxyl radical (OH N , guest molecule). From this analysis, two distinct steps were identified in the recognition process of hydroxyl radical by glutathione: catching and steering, based on the interactions between the host-guest molecules. Over 78% of all interactions are related to the catching mechanism via complex formation between anionic carboxyl groups and the OH radical, hence both terminal residues of GSH serve as recognition sites. The glycine residue has an additional role in the recognition of OH radical, namely the steering. The flexibility of the Gly residue enables the formation of further interactions of other parts of glutathione (e.g. thiol, aand bcarbons) with the lone electron pair of the hydroxyl radical. Moreover, quantum chemical calculations were carried out on selected GSH/OH N complexes and on appropriate GSH conformers to describe the energy profile of the recognition process. The relative enthalpy and the free energy changes of the radical recognition of the strongest complexes varied from 242.4 to 227.8 kJ/mol and from 221.3 to 9.8 kJ/mol, respectively. These complexes, containing two or more intermolecular interactions, would be the starting configurations for the hydrogen atom migration to quench the hydroxyl radical via different reaction channels.
Glutathione revisited: a better scavenger than previously thought
Frontiers in Pharmacology, 2014
Glutathione (GSH) is the classical example of a scavenging antioxidant. It forms the first line of defense and efficiently scavenges reactive species, e.g., hypochlorous acid (HOCl), before they inflict damage to biomolecules. Scavenging antioxidant activity is best established in competition assays (that closely mimics molecular mechanism of the biological effect). In this type of assay, the antioxidant competes with a molecule that functions as an easy read-out detector for a reactive species. It is generally assumed that the scavenging antioxidant activity reflects the reaction rate constant of the antioxidant with the reactive species (k a ). However, critical appraisal of several competition assays of GSH with HOCl as reactive species, reveals that k a does not determine the scavenging antioxidant activity. Assays using acetylcholine esterase, alpha1-antiprotease, methionine, and albumin as detector are compared. The total number of molecules of the reactive species scavenged by GSH plus that by partially oxidized forms of the GSH, reflect the scavenging activity of GSH.The contribution of the partially oxidized forms of GSH depends on the reactivity of the competing molecule. In several assays the partially oxidized forms of GSH have a substantial contribution to the scavenging activity of GSH. In contrast to the prevailing perception, not the reaction rate but rather the total number of molecules of the reactive species scavenged reflects the true scavenging activity of an antioxidant like GSH.
The changing faces of glutathione, a cellular protagonist
Biochemical Pharmacology, 2003
Glutathione (GSH) has been described for a long time just as a defensive reagent against the action of toxic xenobiotics (drugs, pollutants, carcinogens). As a prototype antioxidant, it has been involved in cell protection from the noxious effect of excess oxidant stress, both directly and as a cofactor of glutathione peroxidases. In addition, it has long been known that GSH is capable of forming disulfide bonds with cysteine residues of proteins, and the relevance of this mechanism ("S-glutathionylation") in regulation of protein function is currently receiving confirmation in a series of research lines. Rather paradoxically, however, recent studies have also highlighted the ability of GSH-and notably of its catabolites-to promote oxidative processes, by participating in metal ion-mediated reactions eventually leading to formation of reactive oxygen species and free radicals. A crucial role in these phenomena is played by membrane bound gamma-glutamyltransferase activity. The significance of GSH as a major factor in regulation of cell life, proliferation, and death, should be regarded as the integrated result of all these roles it can play.