glutathione S-transferase

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(GST)

An eukaryotic and prokaryotic phase II metabolic isoenzyme, abundant in the liver. It can catalyze the conjugation of the reduced form of glutathione (GSH) to xenobiotic substrates for the detoxification of numerous endogenous and exogenous compounds.
It is also involved in the phase I detoxification process such as dehydrochlorination of 1,1,1-Trichloro-2,2-bis(p-chlorophenyl) ethane to less toxic 1,l-Dichloro-2,2-bis(p-chlorophenyl) ethylene.
In addition, it may participate in the passive non-catalytic binding of substrates and sequestration, which prevents the binding of xenobiotics to their target proteins.

There are several categories of enzymes involved in the metabolism of lipophilic xenobiotics and their conversions into less toxic compounds exhibiting increased hydrophilicity.
(Phases of metabolic detoxification of xenobiotics)
• Phase I: Oxidation, reduction, and hydrolysis of lipophilic substances carried out by a variety of enzymes.
• Phase II: Conjugation of hydrophilic compounds (i.e. glutathione) to xenobiotics and/or phase I products to produce more hydrophilic products.
• Phase III: Excretion of products of phases I and/or II from cells by multidrug resistance proteins and other ABC transporters.

It catalyses the conjugation of GSH, via a sulfhydryl group, to electrophilic centers on a wide variety of substrates in order to make the compounds more water-soluble, that detoxifies endogenous compounds such as peroxidised lipids and enables the breakdown of xenobiotics.
It may also bind toxins and function as transport proteins.
(Functions)
• Transport and detoxification (neutralization) of bilirubin (toxic catabolite of heme).
• Biosynthesis of icosanoids (e.g. prostaglandins, leukotrienes).
• Catalyzation of the nucleophilic attack of the SH-group of glutathione (GSH) on an electrophilic center of a lipophilic second substrate.

(Subfamilies)
• cytosolic GST: Composes the largest subfamily. Presents in the cytoplasm and soluble. Largely expressed in human liver and detoxifies a variety of endogenous compounds and exogenous xenobiotics, including environmental pollutants, carcinogens, many drugs, and chemotherapeutic agents.
• mitochondrial GST: Mostly found in the mitochondrial matrix and peroxisomes. The primary defense against oxidative damage to mitochondrial membranes by ensuring the reduction of hydroperoxide groups on phospholipids and other lipid peroxides.
• microsomal GST: Belongs to a superfamily of MAPEG (membrane-associated proteins in eicosanoid and glutathione metabolism). Of the 6 human members, 3 are specialized in the synthesis of leukotrienes and prostaglandin E, whereas the others (MGST1-3) have potential roles in drug metabolism. MGST1 conjugates electrophiles and protects from oxidative stress.
• bacterial Fosfomycin-resistance protein: A metallo-enzyme, that inactivates the antibiotic by the addition of nucleophiles such as water, glutathione (GSH), l-cysteine, and bacillithiol (BSH) to the oxirane ring of the molecule.

(Comparison)
• glutathione S-transferase: Catalyses the conjugation of electrophilic substrates to glutathione for detoxification. Acts as a peroxidase and isomerase.
• glutathione peroxidase: Protects the organism from oxidative damage. Reduces lipid hydroperoxides to their corresponding alcohols and free hydrogen peroxides to water.