This view shows enzymes only for those organisms listed below, in the list of taxa known to possess the pathway. If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
|Superclasses:||Degradation/Utilization/Assimilation → Degradation/Utilization/Assimilation - Other|
Expected Taxonomic Range: Opisthokonta
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.
Thiols play several major roles in the cell; they help maintain the redox balance, keeping a reduced environment (see the pathway glutathione redox reactions II), 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 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, a prostaglandin, hepoxilin, nitric oxide, hydroxyalkenals, L-ascorbate, L-dopa, dopamine, and maleate, and it forms thioesters with L-cysteine, coenzyme A, proteins, and other cellular thiols [Wang98h]. In addition, GSH also binds endogenous metals, such as copper, selenium, chromium, and zinc, via nonenzymatic reactions.
The first step is catalyzed by glutathione S-transferase, 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 γ-glutamyl cycle). The GSH-toxin conjugate is transported out of the cell, where it is subsequently degraded by γ-glutamyl hydrolase or γ-glutamyl transpeptidase, and dipeptidases. The breakdown products of the GSH-toxin conjugates (glutamate and glycine) are reabsorbed and can be used for GSH synthesis. The an L-cysteine-S-conjugate 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 [Boyland69]. Mercapturic acids are released into the circulation or bile [Hinchman91]; some are eventually excreted in urine, and some may undergo further metabolism.
A second route for an L-cysteine-S-conjugate is the breakage of the carbon-sulfur bond, catalyzed by cysteine-S-conjugate β-lyase resulting in the formation of thiols, pyruvate and ammonia [Larsen85, Field96, Vuilleumier97, Cooper05]. This enzymatic activity has been shown in both eukaryotes [Seta67] and prokaryotes [Yoshida02a]. 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 an L-cysteine-S-conjugate are possible. It has been shown that these compounds can be substrates for other enzymes, including aminotransferase and L-amino acid oxidase [Cooper05].
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 [Vuilleumier97, Vuilleumier02]. Biochemical evidence for the activity of such enzymes is also abundant. It has also been shown that glutathione conjugates can be metabolized to cysteine conjugates by the action of soil microorganisms, although the specific enzymes involved in the process have not been identified [Field96]. 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 [Larsen85, Yoshida02a].
Cooper05: Cooper AJ, Pinto JT (2005). "Aminotransferase, L-amino acid oxidase and beta-lyase reactions involving L-cysteine S-conjugates found in allium extracts. Relevance to biological activity?." Biochem Pharmacol 69(2);209-20. PMID: 15627473
Hinchman91: Hinchman CA, Matsumoto H, Simmons TW, Ballatori N (1991). "Intrahepatic conversion of a glutathione conjugate to its mercapturic acid. Metabolism of 1-chloro-2,4-dinitrobenzene in isolated perfused rat and guinea pig livers." J Biol Chem 266(33);22179-85. PMID: 1939239
Yoshida02a: Yoshida Y, Nakano Y, Amano A, Yoshimura M, Fukamachi H, Oho T, Koga T (2002). "lcd from Streptococcus anginosus encodes a C-S lyase with alpha,beta-elimination activity that degrades L-cysteine." Microbiology 148(Pt 12);3961-70. PMID: 12480900
Ahmad93: Ahmad H, Singhal SS, Saxena M, Awasthi YC (1993). "Characterization of two novel subunits of the alpha-class glutathione S-transferases of human liver." Biochim Biophys Acta 1161(2-3);333-6. PMID: 8431482
Aigner96: Aigner A, Jager M, Pasternack R, Weber P, Wienke D, Wolf S (1996). "Purification and characterization of cysteine-S-conjugate N-acetyltransferase from pig kidney." Biochem J 317 ( Pt 1);213-8. PMID: 8694766
Blackburn98: Blackburn AC, Woollatt E, Sutherland GR, Board PG (1998). "Characterization and chromosome location of the gene GSTZ1 encoding the human Zeta class glutathione transferase and maleylacetoacetate isomerase." Cytogenet Cell Genet 83(1-2);109-14. PMID: 9925947
BrazierHicks08: Brazier-Hicks M, Evans KM, Cunningham OD, Hodgson DR, Steel PG, Edwards R (2008). "Catabolism of glutathione conjugates in Arabidopsis thaliana. Role in metabolic reactivation of the herbicide safener fenclorim." J Biol Chem 283(30);21102-12. PMID: 18522943
FernandezCanon99: Fernandez-Canon JM, Hejna J, Reifsteck C, Olson S, Grompe M (1999). "Gene structure, chromosomal location, and expression pattern of maleylacetoacetate isomerase." Genomics 58(3);263-9. PMID: 10373324
Grzam07: Grzam A, Martin MN, Hell R, Meyer AJ (2007). "gamma-Glutamyl transpeptidase GGT4 initiates vacuolar degradation of glutathione S-conjugates in Arabidopsis." FEBS Lett 581(17);3131-8. PMID: 17561001
Han09: Han Q, Robinson H, Cai T, Tagle DA, Li J (2009). "Structural insight into the inhibition of human kynurenine aminotransferase I/glutamine transaminase K." J Med Chem 52(9);2786-93. PMID: 19338303
Hirota85: Hirota T, Nishikawa Y, Takahagi H, Igarashi T, Kitagawa H (1985). "Simultaneous purification and properties of dehydropeptidase-I and aminopeptidase-M from rat kidney." Res Commun Chem Pathol Pharmacol 49(3);435-45. PMID: 2865778
Huangpu96: Huangpu J, Pak JH, Graham MC, Rickle SA, Graham JS (1996). "Purification and molecular analysis of an extracellular gamma-glutamyl hydrolase present in young tissues of the soybean plant." Biochem Biophys Res Commun 228(1);1-6. PMID: 8912628
Josch03: Josch C, Klotz LO, Sies H (2003). "Identification of cytosolic leucyl aminopeptidase (EC 22.214.171.124) as the major cysteinylglycine-hydrolysing activity in rat liver." Biol Chem 384(2);213-8. PMID: 12675513
Okuno90: Okuno E, Du F, Ishikawa T, Tsujimoto M, Nakamura M, Schwarcz R, Kido R (1990). "Purification and characterization of kynurenine-pyruvate aminotransferase from rat kidney and brain." Brain Res 534(1-2);37-44. PMID: 1963565
Showing only 20 references. To show more, press the button "Show all references".
©2014 SRI International, 333 Ravenswood Avenue, Menlo Park, CA 94025-3493