Glutathione STransferases GSTs EC 25118

Subcellular location: Soluble GSTs are divided into cytosolic (seven classes) and mitochondrial types. Microsomal GSTs are also known as membrane-associated proteins in eicosanoid and glutathione metabolism (MAPEG).

Cofactor: Glutathione (GSH).

Reaction: Conjugation of GSH to an electrophilic site on the substrate (see Fig. 2.6). The GST enzyme orients the substrate and the GSH in a position that increases nucleophilicity of -SH towards the substrate.

GSH conjugates are excreted in bile and its breakdown product (the N-acetylcysteine (NAC) conjugate or mercapturic acid) is excreted in urine. In the liver, the NAC conjugate is formed by dipeptidases that hydrolyze glycine and glutamate from the GSH conjugate to form a cysteine conjugate. The cysteine conjugate is transported to bile or the blood. In the kidney, N-acetyltransferase (NAT) acetylates the primary amine of cysteine to form the NAC conjugate. Also in the kidney, b-lyase can cleave the carbon-sulfur bond to form a free thiol.

Inhibitor: Ethacrynic acid.

L-Buthionine-sulfoximine (BSO) and acivicin are inhibitors of g-glutamylcysteine synthetase and g-glutamyltranspeptidase, respectively.

Substrates: 1-Chloro-2,4-dinitrobenzene (CDNB) and ethacrynic acid.

GST inhibition is considered an important therapeutic area in oncology because the overexpression of this enzyme in tumors can modulate drug resistance.

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