Glutathione-S-Transferases as Potential Targets for Modulation of Nitric Oxide-Mediated Vasodilation

Abstract

Glutathione-S-transferases (GSTs) are highly promiscuous in terms of their interactions with multiple proteins, leading to various functions. In addition to their classical detoxification roles with multi-drug resistance-related protein-1 (MRP1), more recent studies have indicated the role of GSTs in cellular nitric oxide (NO) metabolism. Vasodilation is classically induced by NO through its interaction with soluble guanylate cyclase. The ability of GSTs to biotransform organic nitrates such as nitroglycerin for NO generation can markedly modulate vasodilation, with this effect being prevented by specific GST inhibitors. Recently, other structurally distinct pro-drugs that generate NO via GST-mediated catalysis have been developed as anti-cancer agents and also indicate the potential of GSTs as suitable targets for pharmaceutical development. Further studies investigating GST biochemistry could enhance our understanding of NO metabolism and lead to the generation of novel and innovative vasodilators for clinical use.

Intermittent hypoxia differentially affects metabolic and oxidative stress responses in two species of cyprinid fish

“…Furthermore, the increase in antioxidant defense in the gill was associated with elevated ROS levels, while the increase in the liver was not linked to changes in ROS levels. Interestingly, our findings revealed concordant variations in GST activity and RNS levels in response to hypoxic conditions in both species, in line with the proposed function of GST in nitric oxide regulation ( Aravilli et al, 2021 ; Russell and Richardson, 2022 ). Neither of the two studied cyprinid species exhibited an increase in oxidative damage to their membranes, proteins, or DNA, suggesting that alterations in ROS and RNS levels caused by hypoxia remain manageable by the antioxidant system's capabilities.…”

Mesenchymal stromal/stem cell tissue source and in vitro expansion impact extracellular vesicle protein and miRNA compositions as well as angiogenic and immunomodulatory capacities

“…For example, changes in CS, a marker for mitochondrial content (Larsen et al., 2012 ), imply a shift in metabolic state with passage number, decreasing for BMSCs and increasing for ASCs at P8. Meanwhile, IDH2 generates NADPH thereby facilitating production of nitric oxide (NO) and cellular antioxidants, which are involved in vasodilation (Russell & Richardson, 2022 ), neurotransmission (Zhu et al., 2021 ), immune responses, and cellular antioxidant defence (Smolková & Ježek, 2012 ). Thus, the opposite changes in IDH2 levels could alter the therapeutic efficacy of P8 BMSC‐EVs and ASC‐EVs in disparate ways.…”

Discovery, SAR Study of GST Inhibitors from a Novel Quinazolin-4(1H)-one Focused DNA-Encoded Library

“…As a vital transferase in the glutathione-binding reaction, GST is widely distributed in the cytoplasm of various types of cells and serves as a key protein for the metabolism of many internal and external toxic substances. , Apart from the versatile antidote, GST is also involved in cell signaling, post-translational modification, and programed cell senescence . In mammalian cells, GST proteins include several subtypes such as α, ζ, θ, μ, π, σ and ω GSTs, and all of them are potential targets for distinct therapeutic areas. − For example, overexpression of GST is considered one of the reasons for multidrug resistance (MDR) in cancer. , GSTs have also been detected in pathogenic helminths. Schistosoma japonicum GST (SjGST), having a similar structure to members of the μ class of cytosolic GSTs (GSTM), has been reported as a potential therapeutic target for schistosomiasis .…”