MGST1

Official Full Name

microsomal glutathione S-transferase 1

Organism

Homo sapiens

GeneID

4257

Background

The MAPEG (Membrane Associated Proteins in Eicosanoid and Glutathione metabolism) family consists of six human proteins, two of which are involved in the production of leukotrienes and prostaglandin E, important mediators of inflammation. Other family members, demonstrating glutathione S-transferase and peroxidase activities, are involved in cellular defense against toxic, carcinogenic, and pharmacologically active electrophilic compounds. This gene encodes a protein that catalyzes the conjugation of glutathione to electrophiles and the reduction of lipid hydroperoxides. This protein is localized to the endoplasmic reticulum and outer mitochondrial membrane where it is thought to protect these membranes from oxidative stress. Several transcript variants, some non-protein coding and some protein coding, have been found for this gene. [provided by RefSeq, May 2012]

Synonyms

MGST; PMAN; GST12; MGST-I;

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Detailed Information

Microsomal glutathione S-transferase (mGST) includes mGST-I, mGST-II, mGST-III, prostaglandin E synthase (PEG synthase), leukotriene C4 synthase (LTC4 synthase), 5-lipoxygenase activating protein (FLAP), etc. The mGST supergene family plays a very important role in the metabolism of exogenous and endogenous compounds. Most of the substrates are fat-soluble electrophilic compounds, which are easier to bind to the substrate than cGST. mGST and cytochrome P-450 enzyme (CYP450) are located on the endoplasmic reticulum membrane. Exogenous compounds catalyzed by P-450 oxidase are metabolized here and detoxified directly under the action of mGST. cGST requires the electrophilic group formed in the microsomes to pass through the microsomal membrane to the cytosol to complete the detoxification process.

mGST is widely distributed in the liver, kidney, lung, small intestine, adrenal gland, testis, heart, spleen and other tissues and organs. Among them, the liver is the most abundant, and several subtypes have been purified from human liver cell microsomes. The mGTI is the main cell in the cell mGST. Rat liver mGST content accounts for about 3.1% of microsomal protein, 4.8% of mitochondrial outer membrane protein. The concentration of mGST in endoplasmic reticulum is about 1 mmol·L-1. The amount of mGST present in the plasma membrane tubules and sinusoidal tubules of the hepatocytes was 2% and 0.5% to 1%, respectively. Mammalian liver mGST concentrations are approximately similar and are not increased by induction of drug enzyme inducers such as phenobarbital. However, the content of mGST in the metabolic tissues and organs such as human fetal adrenal glands is 373% in the liver, while the content of mGST in the adult adrenal glands is only 20% in the liver, suggesting that mGST varies in human development and is closely related to metabolic capacity.

Figure 1. Different classes of glutathione S-transferase. (Smita, K., et al. 2018)

mGST and Drug Metabolism

Many drugs can cause lipid peroxidation. mGST-I functions as GSH-Px and acts as an anti-lipid peroxidation. ctivation of mGST-I may be an effective response to the toxic effects of the body on oxidative stress. The drug containing thiourea structure can transiently activate rat mGST after being metabolized by monooxygenase FMO and CYP450 enzyme, predicting that rat liver mGST can be used as a biological test system for evaluating the relationship between structure and alkylation of thiourea-containing structural compounds in vitro. Prednisolone can increase lipid peroxidation and membrane fluidity of the liver membrane, and reduce liver-binding function mediated by mGST and cGST in rats, thereby increasing sensitivity to toxicants.

The mGST present on the liver microsomal membrane is different from cGST in terms of substrate properties, relative molecular mass, gene arrangement and immunology. Most of the hydrophobic drugs produced by the CYP450 enzyme may remain on the microsomes due to their certain lipophilicity and do not diffuse into the cytosol, resulting in ineffective contact with cGST. These drugs are first activated by phase I metabolic enzymes (such as the CYP450 enzyme) and are primarily inactivated by phase II metabolic enzymes (such as the GST enzyme). Norepinephrine activation mGST-I may be a subsequent reaction based on the cytochrome P-450-dependent monooxygenase system to oxidize norepinephrine to a semi-orthophenylene. Moreover, the antineoplastic alkylating agent BCNU is catalyzed by mGST and cytochrome P-450 monooxygenase to catalyze the denitroation. The cytotoxic reagent, other phenylpropionate, chlorambucil, and carbaryl were inactivated by mGST.

References:

Smita, K. , & Trivedi, P. K. . (2018). Glutathione s-transferases: role in combating abiotic stresses including arsenic detoxification in plants. Frontiers in Plant Science, 9, 751-.
Bräutigam L, Zhang J , Dreij K , et al. MGST1, a GSH transferase/peroxidase essential for development and hematopoietic stem cell differentiation[J]. Redox Biology, 2018:S2213231718301514.
Kelner, M. J. , Diccianni, M. B. , Yu, A. L. , Rutherford, M. R. , Estes, L. A. , & Morgenstern, R. . (2014). Absence of mgst1 mrna and protein expression in human neuroblastoma cell lines and primary tissue. Free Radical Biology and Medicine,69, 167-171.

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