The Enzyme Database

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EC 3.4.19.13     
Accepted name: glutathione γ-glutamate hydrolase
Reaction: (1) glutathione + H2O = L-cysteinylglycine + L-glutamate
(2) a glutathione-S-conjugate + H2O = an (L-cysteinylglycine)-S-conjugate + L-glutamate
Other name(s): glutathionase; γ-glutamyltranspeptidase (ambiguous); glutathione hydrolase; GGT (gene name); ECM38 (gene name)
Comments: This is a bifunctional protein that also has the activity of EC 2.3.2.2, γ-glutamyltransferase. The enzyme binds its substrate by forming an initial γ-glutamyl-enzyme intermediate, releasing the L-cysteinylglycine part of the molecule. The enzyme then reacts with either a water molecule or a different acceptor substrate (usually an L-amino acid or a dipeptide) to form L-glutamate or a product containing a new γ-glutamyl isopeptide bond, respectively. The enzyme acts on glutathione, glutathione-S-conjugates, and, at a lower level, on other substrates with an N-terminal L-γ-glutamyl residue. It plays a crucial part in the glutathione-mediated xenobiotic detoxification pathway. The enzyme consists of two chains that are created by the proteolytic cleavage of a single precursor polypeptide.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc
References:
1.  Hanigan, M.H. and Ricketts, W.A. Extracellular glutathione is a source of cysteine for cells that express γ-glutamyl transpeptidase. Biochemistry 32 (1993) 6302–6306. [PMID: 8099811]
2.  Carter, B.Z., Wiseman, A.L., Orkiszewski, R., Ballard, K.D., Ou, C.N. and Lieberman, M.W. Metabolism of leukotriene C4 in γ-glutamyl transpeptidase-deficient mice. J. Biol. Chem. 272 (1997) 12305–12310. [DOI] [PMID: 9139674]
3.  Suzuki, H. and Kumagai, H. Autocatalytic processing of γ-glutamyltranspeptidase. J. Biol. Chem. 277 (2002) 43536–43543. [DOI] [PMID: 12207027]
4.  Okada, T., Suzuki, H., Wada, K., Kumagai, H. and Fukuyama, K. Crystal structures of γ-glutamyltranspeptidase from Escherichia coli, a key enzyme in glutathione metabolism, and its reaction intermediate. Proc. Natl. Acad. Sci. USA 103 (2006) 6471–6476. [DOI] [PMID: 16618936]
5.  Boanca, G., Sand, A., Okada, T., Suzuki, H., Kumagai, H., Fukuyama, K. and Barycki, J.J. Autoprocessing of Helicobacter pylori γ-glutamyltranspeptidase leads to the formation of a threonine-threonine catalytic dyad. J. Biol. Chem. 282 (2007) 534–541. [DOI] [PMID: 17107958]
6.  Okada, T., Suzuki, H., Wada, K., Kumagai, H. and Fukuyama, K. Crystal structure of the γ-glutamyltranspeptidase precursor protein from Escherichia coli. Structural changes upon autocatalytic processing and implications for the maturation mechanism. J. Biol. Chem. 282 (2007) 2433–2439. [DOI] [PMID: 17135273]
7.  Grzam, A., Martin, M.N., Hell, R. and Meyer, A.J. γ-Glutamyl transpeptidase GGT4 initiates vacuolar degradation of glutathione S-conjugates in Arabidopsis. FEBS Lett. 581 (2007) 3131–3138. [PMID: 17561001]
8.  Wickham, S., West, M.B., Cook, P.F. and Hanigan, M.H. Gamma-glutamyl compounds: substrate specificity of γ-glutamyl transpeptidase enzymes. Anal. Biochem. 414 (2011) 208–214. [DOI] [PMID: 21447318]
9.  Keillor, J.W., Castonguay, R. and Lherbet, C. Gamma-glutamyl transpeptidase substrate specificity and catalytic mechanism. Methods Enzymol. 401 (2005) 449–467. [PMID: 16399402]
[EC 3.4.19.13 created 2011, modified 2019]
 
 
EC 3.4.19.14     
Accepted name: leukotriene-C4 hydrolase
Reaction: leukotriene C4 + H2O = leukotriene D4 + L-glutamate
Other name(s): γ-glutamyl leukotrienase; GGT5
Comments: The mouse enzyme is specific for leukotriene C4, while the human enzyme also has considerable activity towards glutathione and oxidized glutathione (cf. EC 3.4.19.13, glutathione hydrolase) [3-4].
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc
References:
1.  Carter, B.Z., Wiseman, A.L., Orkiszewski, R., Ballard, K.D., Ou, C.N. and Lieberman, M.W. Metabolism of leukotriene C4 in γ-glutamyl transpeptidase-deficient mice. J. Biol. Chem. 272 (1997) 12305–12310. [DOI] [PMID: 9139674]
2.  Shi, Z.Z., Han, B., Habib, G.M., Matzuk, M.M. and Lieberman, M.W. Disruption of γ-glutamyl leukotrienase results in disruption of leukotriene D4 synthesis in vivo and attenuation of the acute inflammatory response. Mol. Cell Biol. 21 (2001) 5389–5395. [DOI] [PMID: 11463821]
3.  Han, B., Luo, G., Shi, Z.Z., Barrios, R., Atwood, D., Liu, W., Habib, G.M., Sifers, R.N., Corry, D.B. and Lieberman, M.W. γ-glutamyl leukotrienase, a novel endothelial membrane protein, is specifically responsible for leukotriene D4 formation in vivo. Am J Pathol 161 (2002) 481–490. [DOI] [PMID: 12163373]
4.  Wickham, S., West, M.B., Cook, P.F. and Hanigan, M.H. Gamma-glutamyl compounds: substrate specificity of γ-glutamyl transpeptidase enzymes. Anal. Biochem. 414 (2011) 208–214. [DOI] [PMID: 21447318]
[EC 3.4.19.14 created 2012]
 
 
EC 4.4.1.20     
Accepted name: leukotriene-C4 synthase
Reaction: leukotriene C4 = leukotriene A4 + glutathione
For diagram of leukotriene biosynthesis, click here
Glossary: leukotriene C4 = (7E,9E,11Z,14Z)-(5S,6R)-6-(glutathion-S-yl)-5-hydroxyicosa-7,9,11,14-tetraenoate
leukotriene A4 = (7E,9E,11Z,14Z)-(5S,6S)-5,6-epoxyicosa-7,9,11,14-tetraenoate
Other name(s): leukotriene C4 synthetase; LTC4 synthase; LTC4 synthetase; leukotriene A4:glutathione S-leukotrienyltransferase; (7E,9E,11Z,14Z)-(5S,6R)-5,6-epoxyicosa-7,9,11,14-tetraenoate:glutathione leukotriene-transferase (epoxide-ring-opening); (7E,9E,11Z,14Z)-(5S,6R)-6-(glutathion-S-yl)-5-hydroxyicosa-7,9,11,14-tetraenoate glutathione-lyase (epoxide-forming)
Systematic name: leukotriene-C4 glutathione-lyase (leukotriene-A4-forming)
Comments: The reaction proceeds in the direction of addition. Not identical with EC 2.5.1.18, glutathione transferase.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, PDB, CAS registry number: 90698-32-1
References:
1.  Bach, M.K., Brashler, J.R. and Morton, D.R., Jr. Solubilization and characterization of the leukotriene C4 synthetase of rat basophil leukemia cells: a novel, particulate glutathione S-transferase. Arch. Biochem. Biophys. 230 (1984) 455–465. [DOI] [PMID: 6324687]
2.  Shimizu, T. Enzymes functional in the syntheses of leukotrienes and related compounds. Int. J. Biochem. 20 (1988) 661–666. [PMID: 2846379]
3.  Lam, B.K. and Austen, K.F. Leukotriene C4 synthase: a pivotal enzyme in cellular biosynthesis of the cysteinyl leukotrienes. Prostaglandins Other Lipid Mediat. 68-69 (2002) 511–520. [DOI] [PMID: 12432940]
4.  Christmas, P., Weber, B.M., McKee, M., Brown, D. and Soberman, R.J. Membrane localization and topology of leukotriene C4 synthase. J. Biol. Chem. 277 (2002) 28902–28908. [DOI] [PMID: 12023288]
[EC 4.4.1.20 created 1989 as EC 2.5.1.37, transferred 2004 to EC 4.4.1.20]
 
 


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