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  • Please note: This is a general detoxification pathway, where the first step can be catalyzed by many different enzymes, collectively known as glutathione transferases, or GSTs. In the first reaction, R may be an aliphatic, aromatic or heterocyclic group, and X may be a sulfate, nitrile or halide group. General Background Thiols play several major roles in the cell; they help maintain the redox balance, keeping a reduced environment (see the pathway |FRAME: GLUT-REDOX-PWY|), they fight reactive oxygen and nitrogen species (ROS and NOS, respectively), and they are involved in the detoxification of many other toxins and stress-inducing factors. In most organisms the major thiol is the tripeptide |FRAME: GLUTATHIONE| (γ-Glu-Cys-Gly, known as GSH). GSH is active against toxins by a process that involves multiple enzymes, and in the case of eukaryotes, occurs across multiple organs. About This Pathway In this important detoxification mechanism GSH binds to electrophilic chemicals, forming conjugates which are exported from the cell. These conjugation reactions have been demonstrated for a multitude of foreign chemicals, as well as endogenous reactive intermediates. GSH has been shown to form thioether conjugates with leukotrienes, |FRAME: Prostaglandins|, hepoxilin, |FRAME: NITRIC-OXIDE|, hydroxyalkenals, |FRAME: ASCORBATE|, |FRAME: L-DIHYDROXY-PHENYLALANINE|, |FRAME: DOPAMINE|, and |FRAME: MALEATE|, and it forms thioesters with |FRAME: CYS|, |FRAME: CO-A|, proteins, and other cellular thiols |CITS: [9755286]|. In addition, GSH also binds endogenous metals, such as copper, selenium, chromium, and zinc, via nonenzymatic reactions. The first step is catalyzed by |FRAME: CPLX-5803|, a family of enzymes found mainly in the cytosol. Once formed, the GSH-toxin conjugates are metabolized by the same degradative enzymes that metabolize GSH (see |FRAME: PWY-4041|). The GSH-toxin conjugate is transported out of the cell, where it is subsequently degraded by |FRAME: HS06361-MONOMER| or |FRAME: CPLX-6042|, and dipeptidases. The breakdown products of the GSH-toxin conjugates (glutamate and glycine) are reabsorbed and can be used for GSH synthesis. The |FRAME: S-Substituted-L-Cysteines| that is left is also transported back into the cell, where it can be metabolized in different ways. One route is the acetylation of the amino group of the cysteinyl residue by intracellular N-acetyltransferases to form the corresponding mercapturic acids (N-acetylcysteine S-conjugates). The addition of the N-acetylcysteine moiety generally increases the compound's polarity and water solubility, and converts neutral compounds to anions, facilitating their transport across cell membranes and their excretion from the organism |CITS: [4892500]|. Mercapturic acids are released into the circulation or bile |CITS: [ 1939239]|; some are eventually excreted in urine, and some may undergo further metabolism. A second route for |FRAME: S-Substituted-L-Cysteines| is the breakage of the carbon-sulfur bond, catalyzed by |FRAME: MONOMER-10303| resulting in the formation of thiols, pyruvate and ammonia |CITS: [4024656][9045797][15627473]|. This enzymatic activity has been shown in both eukaryotes |CITS: [5627473]| and prokaryotes |CITS: [12480900]|. The thiols which are produced in this reaction are most likely oxidized to sulfonates, or methylated to methylsulfinyl or methylsulfonyl derivatives. Yet additional fates for |FRAME: S-Substituted-L-Cysteines| are possible. It has been shown that these compounds can be substrates for other enzymes, including aminotransferase and L-amino acid oxidase |CITS: [15627473]|. While this pathway has been studied in detail in eukaryotes, considerably less in known about bacteria. Recent sequencing projects of bacterial genomes have revealed the presence of numerous glutathione S-transferase genes in many microbes |CITS: [9045797][11876405]|. Biochemical evidence for the activity of such enzymes is also abundant. It seems that bacteria are more likely to continue by the cysteine conjugate lyase route, as there are several reports for this activity in bacteria |CITS: [4024656][12480900]|.
  • REPLACED http://biocyc.org/biopax/biopax-level3#Pathway129789
  • glutathione-mediated detoxification I
  • glutathione-mediated detoxification I
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