Glutathione metabolism

Glutathione metabolism

Glutathione can be found in the cell in oxidized (Glutathione disulfide) and reduced (Glutathione) form. Reduced glutathione can be either directly formed from Glutathione disulfide as the result of activity of Glutathione reductase (GSHR) [1], [2], or from conjugation of L-Cysteinyl-glycine with (L)-Glutamic acid catalyzed by Gamma-glutamyltranspeptidase 1 precursor (GGT1) or by Gamma-glutamyltransferase light chain 2 (GGTL3) [3].

L-Cysteinyl-glycine is formed as a result of glutathione conjugation to the L-Amino acid moiety catalyzed by GGT1 and GGTL3 [3]. This reaction results in formation of Gamma-(L)-glutamyl-aminoacid which is converted by Gamma-glutamylcyclotransferase (GCTG) [4], [5], [6] to the 5-Oxo-(L)-proline and L-Amino acid. 5-Oxo-(L)-proline is then reduced to (L)-Glutamic acid by 5-Oxoprolinase (OPLA) [7], [8], [9], (L)-Glutamic acid also produced in the Glutathione degradation during the R-S-Alanylglycine formation step.

5-Oxo-(L)-proline and (L)-Cysteine are produced as the result of Gamma-(L)-glutamyl-(L)-cysteine cleavage catalyzed by GCTG [6]. Gamma-(L)-glutamyl-(L)-cysteine itself is synthesized by Glutamate-cysteine ligase catalytic subunit (GCL cat) from (L)-Glutamic acid and from (L)-Cysteine [10], [11]. Glutathione synthetase (GSHB) catalyzes subsequent conjugation of Gamma-(L)-glutamyl-(L)-cysteine and Glycine to form Glutathione [12], [13]. Glycine is supplied from L-Cysteinyl-glycine degradation to Glycine and to (L)-Cysteine, as well as from the R-S-Alanylglycine degradation step.

Glutathione (reduced) reacts with various substrates (RX). Those reactions are carried out by a set of enzymes: Glutathione S-transferase A1 (GSTA1), Glutathione S-transferase A2 (GSTA2), Glutathione S-transferase A3 (GSTA3), Glutathione S-transferase A4 (GSTA4), Glutathione S-transferase A5 (GSTA5) [14], [15], [16], [17], [18], [19], Glutathione S-transferase M1 (GSTM1), Glutathione S-transferase M2 (GSTM2) [20], [21], Glutathione S-transferase M3 (GSTM3), Glutathione S-transferase M4 (GSTM4), glutathione S-transferase M5 (GSTM5) [22], [23], [24], [25], [26], [27], Glutathione transferase zeta 1 (maleylacetoacetate isomerase) (MAAI) [28], [29], Glutathione transferase omega-1 (GSTO1), Glutathione transferase omega-2 (GSTO2) [30], [31], Glutathione S-transferase theta-1 (GSTT1), Glutathione S-transferase theta-2 (GSTT2) [32], [33], Glutathione S-transferase kappa 1 (GSTK1) [34], [35], Glutathione S-transferase pi 1 (GSTP1) [36], [37], Microsomal glutathione S-transferase 1 (MGST), Microsomal glutathione S-transferase 2 (MGST2), and Microsomal glutathione S-transferase 3 (MGST3) [27], [38]. These reactions produce R-S-Glutathione (glutathione conjugated to a moiety) products. Subsequently R-S-Glutathione lose their (L)-Glutamic acid moieties in reactions catalyzed by GGT1 and GGTL3 [3] to produce R-S-Alanylglycine that is further degraded to R-S-Alanine by Aminopeptidase N (CD13).

Glutathione disulfide can be formed directly from Glutathione in the reaction catalyzed by Glutathione peroxidase 4 (GPX4 (PHGPx)) [39], Glutathione peroxidase 1 (GPX1) [40], [41], Glutathione peroxidase 2 (GPX2) [42], [43], Glutathione peroxidase 3 (plasma) (GPX3) [44], [45], Glutathione peroxidase 6 (GPX6) [46], [47], Glutathione peroxidase 7 (GPX7), Glutathione peroxidase 5 (GPX5) [48] and GSHR.

Glutathione disulfide can also be formed through ascorbate metabolism.

References:

1. Barker JE, Heales SJ, Cassidy A, Bola?os JP, Land JM, Clark JB
   Depletion of brain glutathione results in a decrease of glutathione reductase activity; an enzyme susceptible to oxidative damage. Brain research 1996 Apr 15;716(1-2):118-22
2. Dickinson DA, Forman HJ
   Glutathione in defense and signaling: lessons from a small thiol. Annals of the New York Academy of Sciences 2002 Nov;973:488-504
3. Leh H, Courtay C, Gerardin P, Wellman M, Siest G, Visvikis A
   Cloning and expression of a novel type (III) of human gamma-glutamyltransferase truncated mRNA. FEBS letters 1996 Oct 7;394(3):258-62
4. Heinle H, Wendel A
   [Does a modified gamma-glutamyl cycle exist in human erythrocytes (author's transl)]. Hoppe-Seyler's Zeitschrift fur physiologische Chemie 1976 Nov;357(11):1459-63
5. Fink ML, Chung SI, Folk JE
   gamma-Glutamylamine cyclotransferase: specificity toward epsilon-(L-gamma-glutamyl)-L-lysine and related compounds. Proceedings of the National Academy of Sciences of the United States of America 1980 Aug;77(8):4564-8
6. Danson JW, Trawick ML, Cooper AJ
   Spectrophotometric assays for L-lysine alpha-oxidase and gamma-glutamylamine cyclotransferase. Analytical biochemistry 2002 Apr 15;303(2):120-30
7. Srivenugopal KS, Ali-Osman F
   Activity and distribution of the cysteine prodrug activating enzyme, 5-oxo-L-prolinase, in human normal and tumor tissues. Cancer letters 1997 Jul 15;117(1):105-11
8. Chen X, Schecter RL, Griffith OW, Hayward MA, Alpert LC, Batist G
   Characterization of 5-oxo-L-prolinase in normal and tumor tissues of humans and rats: a potential new target for biochemical modulation of glutathione. Clinical cancer research : an official journal of the American Association for Cancer Research 1998 Jan;4(1):131-8
9. Weber P, Jager M, Bangsow T, Knell G, Piechaczek K, Koch J, Wolf S
   Kinetic parameters and tissue distribution of 5-oxo-L-prolinase determined by a fluorimetric assay. Journal of biochemical and biophysical methods 1999 Jan 13;38(1):71-82
10. Sriram R, Ali-Osman F
    Purification and biochemical characterization of gamma-glutamylcysteine synthetase from a human malignant astrocytoma cell line. Biochemistry and molecular biology international 1993 Aug;30(6):1053-60
11. Misra I, Griffith OW
    Expression and purification of human gamma-glutamylcysteine synthetase. Protein expression and purification 1998 Jul;13(2):268-76
12. Beutler E, Gelbart T
    Improved assay of the enzymes of glutathione synthesis: gamma-glutamylcysteine synthetase and glutathione synthetase. Clinica chimica acta; international journal of clinical chemistry 1986 Jul 15;158(1):115-23
13. Ristoff E, Hebert C, Nj?lsson R, Norgren S, Rooyackers O, Larsson A
    Glutathione synthetase deficiency: is gamma-glutamylcysteine accumulation a way to cope with oxidative stress in cells with insufficient levels of glutathione? Journal of inherited metabolic disease 2002 Nov;25(7):577-84
14. Stenberg G, Bjornestedt R, Mannervik B
    Heterologous expression of recombinant human glutathione transferase A1-1 from a hepatoma cell line. Protein expression and purification 1992 Feb;3(1):80-4
15. Ahmad H, Singhal SS, Saxena M, Awasthi YC
    Characterization of two novel subunits of the alpha-class glutathione S-transferases of human liver. Biochimica et biophysica acta 1993 Feb 13;1161(2-3):333-6
16. Pulford DJ, Hayes JD
    Characterization of the rat glutathione S-transferase Yc2 subunit gene, GSTA5: identification of a putative antioxidant-responsive element in the 5'-flanking region of rat GSTA5 that may mediate chemoprotection against aflatoxin B1. The Biochemical journal 1996 Aug 15;318 ( Pt 1):75-84
17. Hubatsch I, Ridderstrom M, Mannervik B
    Human glutathione transferase A4-4: an alpha class enzyme with high catalytic efficiency in the conjugation of 4-hydroxynonenal and other genotoxic products of lipid peroxidation. The Biochemical journal 1998 Feb 15;330 ( Pt 1):175-9
18. Johansson AS, Mannervik B
    Human glutathione transferase A3-3, a highly efficient catalyst of double-bond isomerization in the biosynthetic pathway of steroid hormones. The Journal of biological chemistry 2001 Aug 31;276(35):33061-5
19. Tetlow N, Liu D, Board P
    Polymorphism of human Alpha class glutathione transferases. Pharmacogenetics 2001 Oct;11(7):609-17
20. Vorachek WR, Pearson WR, Rule GS
    Cloning, expression, and characterization of a class-mu glutathione transferase from human muscle, the product of the GST4 locus. Proceedings of the National Academy of Sciences of the United States of America 1991 May 15;88(10):4443-7
21. Ross VL, Board PG
    Molecular cloning and heterologous expression of an alternatively spliced human Mu class glutathione S-transferase transcript. The Biochemical journal 1993 Sep 1;294 ( Pt 2):373-80
22. Klone A, Hussnatter R, Sies H
    Cloning, sequencing and characterization of the human alpha glutathione S-transferase gene corresponding to the cDNA clone pGTH2. The Biochemical journal 1992 Aug 1;285 ( Pt 3):925-8
23. Tsuchida S, Maki T, Sato K
    Purification and characterization of glutathione transferases with an activity toward nitroglycerin from human aorta and heart. Multiplicity of the human class Mu forms. The Journal of biological chemistry 1990 May 5;265(13):7150-7
24. Alin P, Mannervik B, Jornvall H
    Structural evidence for three different types of glutathione transferase in human tissues. FEBS letters 1985 Mar 25;182(2):319-22
25. Zhong S, Spurr NK, Hayes JD, Wolf CR
    Deduced amino acid sequence, gene structure and chromosomal location of a novel human class Mu glutathione S-transferase, GSTM4. The Biochemical journal 1993 Apr 1;291 ( Pt 1):41-50
26. Takahashi Y, Campbell EA, Hirata Y, Takayama T, Listowsky I
    A basis for differentiating among the multiple human Mu-glutathione S-transferases and molecular cloning of brain GSTM5. The Journal of biological chemistry 1993 Apr 25;268(12):8893-8
27. Jakobsson PJ, Mancini JA, Ford-Hutchinson AW
    Identification and characterization of a novel human microsomal glutathione S-transferase with leukotriene C4 synthase activity and significant sequence identity to 5-lipoxygenase-activating protein and leukotriene C4 synthase. The Journal of biological chemistry 1996 Sep 6;271(36):22203-10
28. Tong Z, Board PG, Anders MW
    Glutathione transferase zeta catalyses the oxygenation of the carcinogen dichloroacetic acid to glyoxylic acid. The Biochemical journal 1998 Apr 15;331 ( Pt 2):371-4
29. Polekhina G, Board PG, Blackburn AC, Parker MW
    Crystal structure of maleylacetoacetate isomerase/glutathione transferase zeta reveals the molecular basis for its remarkable catalytic promiscuity. Biochemistry 2001 Feb 13;40(6):1567-76
30. Board PG, Coggan M, Chelvanayagam G, Easteal S, Jermiin LS, Schulte GK, Danley DE, Hoth LR, Griffor MC, Kamath AV, Rosner MH, Chrunyk BA, Perregaux DE, Gabel CA, Geoghegan KF, Pandit J
    Identification, characterization, and crystal structure of the Omega class glutathione transferases. The Journal of biological chemistry 2000 Aug 11;275(32):24798-806
31. Whitbread AK, Tetlow N, Eyre HJ, Sutherland GR, Board PG
    Characterization of the human Omega class glutathione transferase genes and associated polymorphisms. Pharmacogenetics 2003 Mar;13(3):131-44
32. Mainwaring GW, Williams SM, Foster JR, Tugwood J, Green T
    The distribution of theta-class glutathione S-transferases in the liver and lung of mouse, rat and human. The Biochemical journal 1996 Aug 15;318 ( Pt 1):297-303
33. Rossjohn J, McKinstry WJ, Oakley AJ, Verger D, Flanagan J, Chelvanayagam G, Tan KL, Board PG, Parker MW
    Human theta class glutathione transferase: the crystal structure reveals a sulfate-binding pocket within a buried active site. Structure (London, England : 1993) 1998 Mar 15;6(3):309-22
34. Morel F, Rauch C, Petit E, Piton A, Theret N, Coles B, Guillouzo A
    Gene and protein characterization of the human glutathione S-transferase kappa and evidence for a peroxisomal localization. The Journal of biological chemistry 2004 Apr 16;279(16):16246-53
35. Li J, Xia Z, Ding J
    Thioredoxin-like domain of human kappa class glutathione transferase reveals sequence homology and structure similarity to the theta class enzyme. Protein science : a publication of the Protein Society 2005 Sep;14(9):2361-9
36. Singh SV, Ahmad H, Kurosky A, Awasthi YC
    Purification and characterization of unique glutathione S-transferases from human muscle. Archives of biochemistry and biophysics 1988 Jul;264(1):13-22
37. Ali-Osman F, Akande O, Antoun G, Mao JX, Buolamwini J
    Molecular cloning, characterization, and expression in Escherichia coli of full-length cDNAs of three human glutathione S-transferase Pi gene variants. Evidence for differential catalytic activity of the encoded proteins. The Journal of biological chemistry 1997 Apr 11;272(15):10004-12
38. DeJong JL, Morgenstern R, Jornvall H, DePierre JW, Tu CP
    Gene expression of rat and human microsomal glutathione S-transferases. The Journal of biological chemistry 1988 Jun 15;263(17):8430-6
39. Lin MT, Beal MF
    Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 2006 Oct 19;443(7113):787-95
40. White AR, Collins SJ, Maher F, Jobling MF, Stewart LR, Thyer JM, Beyreuther K, Masters CL, Cappai R
    Prion protein-deficient neurons reveal lower glutathione reductase activity and increased susceptibility to hydrogen peroxide toxicity. The American journal of pathology 1999 Nov;155(5):1723-30
41. Tam NN, Gao Y, Leung YK, Ho SM
    Androgenic regulation of oxidative stress in the rat prostate: involvement of NAD(P)H oxidases and antioxidant defense machinery during prostatic involution and regrowth. The American journal of pathology 2003 Dec;163(6):2513-22
42. Maiorino M, Chu FF, Ursini F, Davies KJ, Doroshow JH, Esworthy RS
    Phospholipid hydroperoxide glutathione peroxidase is the 18-kDa selenoprotein expressed in human tumor cell lines. The Journal of biological chemistry 1991 Apr 25;266(12):7728-32
43. Chu FF, Doroshow JH, Esworthy RS
    Expression, characterization, and tissue distribution of a new cellular selenium-dependent glutathione peroxidase, GSHPx-GI. The Journal of biological chemistry 1993 Feb 5;268(4):2571-6
44. Chu FF, Esworthy RS, Doroshow JH, Doan K, Liu XF
    Expression of plasma glutathione peroxidase in human liver in addition to kidney, heart, lung, and breast in humans and rodents. Blood 1992 Jun 15;79(12):3233-8
45. Esworthy RS, Chu FF, Paxton RJ, Akman S, Doroshow JH
    Characterization and partial amino acid sequence of human plasma glutathione peroxidase. Archives of biochemistry and biophysics 1991 May 1;286(2):330-6
46. Kryukov GV, Castellano S, Novoselov SV, Lobanov AV, Zehtab O, Guigo R, Gladyshev VN
    Characterization of mammalian selenoproteomes. Science (New York, N.Y.) 2003 May 30;300(5624):1439-43
47. De Vega L, Perez Fernandez R, Martin Mateo MC, Bustamante J, Bustamante A, Herrero AM, Bustamante Munguira E
    Study of the activity of glutathione-peroxidase, glutathione-transferase, and glutathione-reductase in renal transplants. Transplantation proceedings 2003 Jun;35(4):1346-50
48. Hall L, Williams K, Perry AC, Frayne J, Jury JA
    The majority of human glutathione peroxidase type 5 (GPX5) transcripts are incorrectly spliced: implications for the role of GPX5 in the male reproductive tract. The Biochemical journal 1998 Jul 1;333 ( Pt 1):5-9