Revisiting the scavenging activity of glutathione: Free radicals diversity and reaction mechanisms

Glutathione (GSH) is the most abundant low-molecular-mass thiolated compound in plants and animals, highly relevant in humans since it is one of the principal antioxidant agents capable of scavenging reactive oxygen species (ROS). In addition, it has a function in the immune system and in cell proliferation, and most recently it was discovered that it works against COVID-19. Considering the high flexibility of glutathione, with an atomic configuration and charge state susceptible to minimal changes in its chemical environment, it is of relevance to ascertain what is the scavenging capacity of each of the most probable glutathione species under physiological conditions. In order to find the site and mechanism that contributes the most to the antioxidant activity of GSH, density functional theory (DFT) calculations on multiple species of this molecule were performed in this work. Reactivity indexes, related to hydrogen atom transfer (HAT), single electron transfer-proton transfer (SET-PT), and sequential proton loss electron transfer (SPLET) mechanism were calculated for glutathione. In addition, Gibbs free energies of reaction (ΔG) were obtained for the reactions of GSH with several free radicals to confirm the thermochemical viability of each antioxidant mechanism and to avoid misleading conclusions in terms of considering energetically unfavorable reactions. The results confirm that HAT is the chemical route contributing the most to the antioxidant activity of GSH. However, at least for one radical of interest, SPLET should also be considered.