The catalytic function of glutathione S-transferase enzymes is to bring the substrate and reduced glutathione into close proximity. Each GST subunit is composed of seven or eight alpha helices and four beta sheets that produce two distinct domains. The N-terminal thirodoxin-like domain that contain the G-site that bind the glutathione and larger C-terminal alpha helical domain containing the H-site that bind the substrate(Armstrong, 1991). The active site residue is a serine in the classes Delta, Epsilon, Theta and Zeta GSTs, while in the Omega class this residue is found to be a cysteine. In most ost of mammalians GSTs have a tyrosine as active site residue Most GST enzymes catalyse intracellular conjugation between reduced glutathione (GSH) and a wide range of exogenous and endogenous compounds, making them more soluble to facilitate their excretion.The conjuguaison of reduced glutathione GSH with xenobiotic allow its removal outside from the cell by transport protein such as multi-drug resistance associated protein The extracellular glutathione conjugate is then cleaved by γ-glutamyltransferase and either aminopeptidase M or cysteinlglycine dipeptidase to produce a cysteinyl conjugate, which is transported back into the cell. This final conjugate is N-acetylted to produce mercapturic acid which is then excreted from the body through urine. (Wand and Ballatori, 1998)
Some GST enzymes also exhibit non-catalytic functions such as non-substrate ligand binding and intracellular transportation of chemicals and stress signal processing.Cytosolic GSTs are considered to be antioxidant because of their role in the neutralization of reactive oxygen species derived from the metabolism of macromolecules (Mannervik,1986). There are report of a few cytosolic GSTs involved in the synthesis and inactivation of prostaglandins. GSTs also play a crucial role in the isomerisation of many biologically important molecules. For example the conversion of 13-cis-retinoic acid to all-trans– retinoic acid is catalyzed by GSTs enzymes. GSTs enzymes also display a non catalytic bindings to reactive metabolites. It is widely thought that GSTs enzymes sequester genotoxic compounds in asuicide type of reaction that prevent xenobiotics from interacting with DNA (Hayes et al., 2001). Despites their positive role of protecting the body GST enzymes cause significant problems in cancer therapy. For instance many researches suggest that GSTs overexpression in tumors is an important mechanism of acquired resistance to cancer chemotherapeutic agents There are no report of MAPEG enzymes being associate with detoxification reactions but are rather involved in the biosynthesis of leukotrienes, prostanoids, and endogenous lipid signaling molecules (Jakobsson et al., 1996).
GSTs enzymes in the phase II detoxification pathway
Phase II detoxification reactions consist principally of conjugation reaction between reactive substrate and endogenous conjugating agents to make them less toxic and water soluble so that they can be excreted from the body. In this view GSTs enzymes play a central role in preserving homeostasis, and maintaining life. Glutathione s-transferases are involved in the metabolism of a wide variety of electrolytic substrates that include antibiotics, vasodilatators, herbicides, insecticides, anti-cancer drugs and carcinogens. GSTs enzymes catalyze the initial reaction in the biosynthesis of mercapturic acid. Interest in insect GSTs has primarily focused on their role in insecticide resistance. Insects GSTs have been implicated to insecticide resistance to insecticides through direct metabolism of the insecticide (Wei et al., 2001), sequestration (Kostaropoulos et al., 2001) or by protecting against the toxic effects of lipids peroxidation products (Vontas et al., 2001). Members of the Delta and Epsilon classes have frequently been associated with insecticide resistance. GST-mediated resistance to organophosphates occurs principally through the conjuguaison of GSH to these insecticides followed by O-dealkylation or O-dearylation as reported in many organophosphates resistant insect species (Oppenoorth et al., 1979; Ugaki et al., 1985). In the house fly, it has been shown that DDT resistance was acquired by GST-mediated dehydrochlorination (Clark and Shamaan, 1984). Ding et al. (2003) reported the AgGSTE2 belonging to Epsilon class as responsible for DDT resistance from East Africa. GSTs may also protect against insecticides by binding these molecules thereby reducing the amount of insecticide that reach the target site (Kostaropoulos et al., 2001). Increased GST activity was also observed in S. furcifera strains exposed to fipronil and synergists (Zhou et al.,2013).