Glutathione S-Transferases - A Review

Abstract

The Glutathione S-transferases (GSTs) form a group of multi-gene isoenzymes involved in the cellular detoxification of both xenobiotic and endobiotic compounds. GSTs have been divided into a number of subclasses, alpha (α), mu {μ), pi (π), and theta (θ). The classification was made on the basis of sequence similarity and immunological cross-reactivity. GSTs show a high level of specificity toward GSH but the electrophilic second substrate can vary significantly both between and within the classes in spite of their sequence similarity. X-ray crystallography and site-directed mutagenesis studies have together elucidated the structure and mechanism of GSTs. Catalysis occurs by conjugation with glutathione (GSH) and the less toxic and more hydrophilic products can then be partially metabolised and excreted. This invaluable service is however disadvantageous during chemotherapy where GSTs have been associated with multi-drug resistance of tumour cells. Levels of expression of different isoforms of GSTs are tissue specific. The variations in expression between normal and tumour cells are of interest and in most cases the levels of GSTs are increased, especially n-GST. Understanding the complex role that GSTs play in drug resistance begins with determining the pattern of isoform expression and the substrate specificities of each isoform. The use of isozyme-specific, GSH analogues as inhibitors to modulate GST activity during chemotherapy is a promising strategy in the battle against cancer. This review attempts to provide a detailed overview of the literature concerning the different classes of GSTs, their function and mechanism and the use of GSTs as therapeutic targets for disease as current at the time of submission.

Enzyme-Activated Fluorogenic Probes for Live-Cell and in Vivo Imaging

“…Glutathione Stransferase (GST) is an important enzyme for the detoxification of xenobiotic substances through the transfer of glutathione for subsequent metabolic decomposition. 60 The structural variety of encountered xenobiotics exerts evolutionary pressure toward either a few enzymes with high substrate promiscuity or many substrate-specific enzymes. Ultimately, multiple isoforms of human GST evolved, with at least eight subclasses present in varied cellular locations, including the cytosol, mitochondria, and microsomes.…”

“…Ultimately, multiple isoforms of human GST evolved, with at least eight subclasses present in varied cellular locations, including the cytosol, mitochondria, and microsomes. 60 These defensive enzymes are also frequently commandeered by cancer cells to acquire drug resistance. GST catalyzes nucleophilic aromatic substitution of glutathione into probe 24 to form a Meisenheimer complex, which collapses to release the parent fluorophore.…”

“…Glutathione S -transferase (GST) is an important enzyme for the detoxification of xenobiotic substances through the transfer of glutathione for subsequent metabolic decomposition . The structural variety of encountered xenobiotics exerts evolutionary pressure toward either a few enzymes with high substrate promiscuity or many substrate-specific enzymes.…”

Contribution of Glutathione S-Transferases to Imidacloprid Resistance in Nilaparvata lugens

“…GSTs catalyze the conjugation of glutathione (GSH) to electrophilic compounds with diverse structures, including xenobiotics and physiological substances. 1 In insects, GSTs play important roles in the detoxification of xenobiotic compounds, such as insecticides and plant allelochemicals. 2−4 Another key role of GSTs in insects is the mediation of oxidative stress responses.…”

“…Glutathione S-transferase (GST, EC2.5.1.18) is a superfamily of multifunctional enzymes, widely distributed in living organisms. GSTs catalyze the conjugation of glutathione (GSH) to electrophilic compounds with diverse structures, including xenobiotics and physiological substances . In insects, GSTs play important roles in the detoxification of xenobiotic compounds, such as insecticides and plant allelochemicals. − Another key role of GSTs in insects is the mediation of oxidative stress responses. , Insect GSTs confer resistance to insecticide via direct metabolism but also indirectly by providing protection against oxidative stress induced by insecticide exposure .…”