The role of glutathione S-transferases in human disease pathogenesis and their current inhibitors

Abstract

Glutathione S-transferases (GSTs) are a family of enzymes detoxifying various harmful compounds by conjugating them with glutathione. While primarily beneficial, dysregulation of GST activity or specific isoforms can contribute to disease pathogenesis. The intricate balance of detoxification processes regulated by GSTs is pivotal in cellular homeostasis, whereby dysregulation in these mechanisms can have profound implications for human health. Certain GSTs neutralize carcinogens, shielding cells and potentially preventing tumorigenesis. Polymorphisms in specific GSTs may result in the accumulation of toxic metabolites, exacerbating oxidative stress, inflammation, and DNA damage, notably observed in neurodegenerative diseases like Parkinson's disease. They can also modulate signaling pathways involved in cell proliferation, survival, and apoptosis, with aberrant activity potentially contributing to uncontrolled cell growth and resistance to cell death, thus promoting cancer development. They may also contribute to autoimmune diseases and chronic inflammatory conditions. This knowledge is useful for designing therapeutic interventions and understanding chemoresistance due to GST polymorphisms. A variety of GST inhibitors have been developed and investigated, with researchers actively working on new inhibitors aimed at preventing off-target effects. By leveraging knowledge of the involvement of specific GST isoforms in disease pathogenesis across different populations, more effective and targeted therapeutics can be designed to enhance patient care and improve treatment outcomes.

Keywords: Drug metabolism; Environmental toxins; Genetic variations; Glutathione S-transferases; Oxidative stress.

Figure 1

Structure and features of the GSTA1 protein (A) Three-dimensional dimeric structure of the human GST (PDB ID:1K3O), colored by chains A (green) and B (brown). N and C terminals are labeled by “N-" and “C-", respectively. (B) SS depicts secondary stricture. Helices are shown in orange barrels and strands in green arrows. Two major domains, the N-terminal TRX-fold domain, and the C-terminal alpha-helical domain are present, with an active site located in a cleft between the two domains. GSTA1, glutathione S-transferase alpha 1; GST, glutathione S-transferase; GSH, glutathione.

Figure 2

Glutathione S-transferase (GST) mediated detoxification pathway in Homo sapiens. R-X is the compound for degradation, where R represents a diverse range of groups, including aliphatic, aromatic, or heterocyclic moieties, while X may denote a sulfate, nitrile, halide group, or even a proton in the reaction. Figure adapted from the MetCyc database (https://biocyc.org/META/NEW-IMAGE?type=PATHWAY&object=PWY-4061&detail-level=3&ENZORG=TAX-9606&EXP-ONLY=NIL; retrieved 10 February 2024). Distinct GST isozymes exist for rats and mice while a multidrug resistance protein (Abcc1) is present before l-glutamate production in the rat detoxification pathway, indicating a unique aspect of their detoxification mechanism. Mice use folate hydrolase Folh1 and γ-glutamyl hydrolase Ggh instead of GGT1 and GGT5 in humans, while these are missing in the rat pathway. Additionally, while aminopeptidases are common to both mice and humans, they are absent in rats, suggesting variations in protein metabolism. Furthermore, kynurenine aminotransferases (KYAT1 and KYAT3) and N-acetyltransferase (NAT8) are present in humans but not in either rodent species, underscoring significant metabolic differences that could impact toxicological and pharmacological studies.