Current Status of the γ-Glutamyl Cycle

  • A. Meister
Part of the Proceedings in Life Sciences book series (LIFE SCIENCES)


According to the γ-Glutamyl cycle, the first step in glutathione breakdown is catalyzed by γ-Glutamyl transpeptidase, which transfers the γ-Glutamyl moiety of glutathione to an acceptor amino acid to form a γ-Glutamyl amino acid. γ-Glutamyl amino acids may be hydrolyzed, participate themselves in transpeptidation, or be converted by γ-Glutamyl cyclotransferase to 5-oxoproline and the corresponding amino acids. 5–0xoproline is converted to glutamate in a reaction coupled with ATP cleavage to ADP and inorganic phosphate. Cysteinyl-glycine, formed in the transpeptidation reaction, is split to cysteine and glycine. Glutamate, cysteine, and glycine are converted to glutathione in two successive steps catalyzed, respectively, by γ-Glutamylcysteine and glutathione synthetases. Metabolite labeling studies and experiments with specific inhibitors that block the cycle at various steps showed that the reactions of the cycle take place in vivo. Studies with enzyme inhibitors and other data, including information obtained from observations on patients with inborn blocks of the cycle, indicate that the γ-Glutamyl cycle accounts for the turnover of intracellular glutathione and functions as one of the systems that mediates translocation of amino acids. Recent in vivo studies on the effect of amino acid administration on glutathione and 5-oxoproline levels, and on the effects of specific inhibition of glutathione synthesis and γ-Glutamyl transpeptidase indicate that there is a physiologically significant connection between the metabolism of glutathione and amino acid transport.


Amino Acid Transport Intracellular Glutathione Mercapturic Acid Glutathione Synthetase Extracellular Amino Acid 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Adamson, E.D., Szewczuk, A., Connell, G.E.: Purification and properties of γ-glutamyl cyclotransferase from Dig liver. Canad. J. Biochem. 49, 218–226 (1971)Google Scholar
  2. 2.
    Boyland, E.: Mercapturic acid conjugation. Proc. 1st Int. Pharmacol. Meeting 1961, 16, 65–76 (1963)Google Scholar
  3. 3.
    Bridges, R.J., Griffith, O.W.: γ-Glutamyl cyclotransferase-inhibition studies in vitro and in vivo using β-aminoglutaryl-L-α-aminobutyrate. Federation Proc. 37, 388 (1978)Google Scholar
  4. 4.
    Connell, G.E., Hanes, C.S.: Enzymic formation of pyrrolidone carboxylic acid from γ-Glutamyl peptides. Nature (London) 177, 377–378 (1956)CrossRefGoogle Scholar
  5. 5.
    Gass, J.D., Meister, A.: Computer analysis of the active site of glutamine synthetase. Biochemistry 9, 1380–1390 (1970)PubMedCrossRefGoogle Scholar
  6. 6.
    Arias, I.M., Jakoby, W.B. (eds.): Glutathione; metabolism and function. Krok Foundation Series, Vol.6, New York: Raven Press 1976Google Scholar
  7. 7.
    Griffith, O.W., Anderson, M.E., Meister, A.: Inhibition of glutathione biosynthesis by prothionine sulfoximine (S-n-propyl-homocysteine sulfoximine), a selective inhibitor of γ-Glutamylcysteine synthetase. J. Biol. Chem. 254 (1979)Google Scholar
  8. 8.
    Griffith, O.W., Bridges, R.J., Meister, A.: Evidence that the γ-Glutamyl cycle functions in vivo using intracellular glutathione: Effects of amino acids and selective inhibition of enzymes. Proc. Natl. Acad. Sci. U.S., 75. (No.11) (1978)Google Scholar
  9. 9.
    Griffith, O.W., Meister, A.: Dependence of energy coupling on nucleotide base structure in the reaction catalyzed by 5-oxo-prolinase. Biochem. Biophys. Res. Commun. 70, 759–765 (1976)PubMedCrossRefGoogle Scholar
  10. 10.
    Griffith, O.W., Meister, A.: Selective inhibition of γ-Glutamyl-cycle enzyme by substrate analogs. Proc. Natl. Acad. Sci. U.S.A. 74, 3330–3334 (1977)PubMedCrossRefGoogle Scholar
  11. 11.
    Griffith, O.W., Meister, A.: Differential inhibition of glutamine and γ-Glutamylcysteine synthetases by α-alkyl analogs of methionine sulfoximine that induce convulsions. J. Biol. Chem. 253, 2333–2338 (1978)PubMedGoogle Scholar
  12. 12.
    Griffith, O.W., Meister, A.: unpublishedGoogle Scholar
  13. 13.
    Griffith, O.W., Meister, A.: unpublishedGoogle Scholar
  14. 14.
    Griffith, O.W., Van Der Werf, P., Meister, A.: Specificity and mechanism of action of 5-oxoprolinase, glutathione: metabolism and function. Arias, I.M., Jakoby, W.B. (eds.), Krok Foundation Symposium, Santa Barbara, California. June 1–3, 1975; pp.63–69. New York: Raven Press 1976Google Scholar
  15. 15.
    Hahn, R., Wendel, A., Flohé, L.: The fate of extracellular glutathione in the rat. Biochim. Biophys. Acta 539, 324–337 (1978)PubMedGoogle Scholar
  16. 16.
    Hanes, C.S., Hird, F.J.R., Isherwood, F.A.: Enzymatic transpeptidation reactions involving γ-Glutamyl peptides and α-aminoacyl peptides. Biochem. J. 51, 25–35 (1952)PubMedGoogle Scholar
  17. 17.
    Heinz, E.: Transport of amino acids by animal cells. In: Metabolic pathways. Hokin, L.F. (ed.), 6, 455–501. New York: Academic Press 1972Google Scholar
  18. 18.
    Hughey, R.P., Rankin, B.A., Elce, J.S., Curthoys, N.P.: Specificity of a particulate rat renal peptidase and its localization along with other enzymes of mercapturic acid synthesis. Arch. Biochem. Biophys. 186, 211–217 (1978)PubMedCrossRefGoogle Scholar
  19. 19.
    Kanazawa, A., Sano, I.: The distribution of γ-L-glutamyl-L-glutamine in mammalian tissues. J. Neurochem. 14, 596–598 (1967)PubMedCrossRefGoogle Scholar
  20. 20.
    Konrad, P.N., Richards, F., Valentine, W.N., Paglia, D.E.: γ-Glutamylcysteine synthetase deficiency. A cause of hereditary hemolytic anemia. N. Engl. J. Med. 286, 557–561 (1972)PubMedCrossRefGoogle Scholar
  21. 21.
    Kuhlenschmidt, T., Curthoys, N.P.: Subcellular localization of rat kidney phosphate independent glutaminase. Arch. Biochem. Biophys. 167, 519–524 (1975)PubMedCrossRefGoogle Scholar
  22. 22.
    Maack, T., Johnson, V., Tate, S.S., Meister, A.: Effects of amino acids on the function of the isolated perfused rat kidney. Federation Proc. 33, 305 (1974)Google Scholar
  23. 23.
    Majerus, P.W., Brauner, M.J., Smith, M.B., Minnick, V.J.: Glutathione synthesis in human erythrocytes. II. Purification and properties of the enzymes of glutathione biosynthesis. J. Clin. Invest. 50, 1637–1643 (1971)PubMedCrossRefGoogle Scholar
  24. 24.
    Meister, A.: On the enzymology of amino acid transport. Science 180, 33–39 (1973)PubMedCrossRefGoogle Scholar
  25. 25.
    Meister, A.: The γ-Glutamyl cycle; diseases associated with specific enzymatic deficiencies. Ann. Int. Med. 81, 247–253 (1974)PubMedGoogle Scholar
  26. 26.
    Meister, A.: 5-oxoprolinuria (pyroglutamic aciduria) and other disorders of glutathione biosynthesis. In: The metabolic basis of inherited diseases, 4th ed. Stanbury, J.B., Wyngaarden, J.B., Frederickson, D.S. (eds.). Chap.16; pp. 328–336. New York: McGraw-Hill 1977Google Scholar
  27. 27.
    Meister, A., Bukenberger, M.W., Strassburger, M.: The optically specific enzymatic cyclization of D-glutamate. Biochem. Z. (Otto Warburg Festband) 338, 217–229 (1963)Google Scholar
  28. 28.
    Meister, A., Tate, S.S.: Glutathione and related γ-Glutamyl compounds; biosynthesis and utilization. Ann. Rev. Biochem. 45, 559–604 (1976)PubMedCrossRefGoogle Scholar
  29. 29.
    Meister, A., Tate, S.S., Ross, L.L.: Membrane-bound γ-Glutamyl transpeptidase. In: The enzymes of biological membranes. Martinosi, A. (ed.). 3, 315–347. New York: Plenum 1976Google Scholar
  30. 30.
    Meister, A., Tate, S.S., Thompson, G.: On the function of the γ-Glutamyl cycle in the transport of amino acids and peptides, pp. 123–143. CIBA Foundation Symposium on Peptide Transport and Hydrolysis, London; Nov. 1976 (1977)Google Scholar
  31. 31.
    Mooz, E. Dodd, Meister, A.: Tripeptide (glutathione) synthetase; purification properties, and mechanism of action. Biochemistry 6, 1722–1734 (1967)PubMedCrossRefGoogle Scholar
  32. 32.
    Novogrodsky, A., Tate, S.S., Meister, A.: γ-Glutamyl transpeptidase. A lymphoid cell-surface marker; relationship to blastogenesis, differentiation, and neoplasia. Proc. Natl. Acad. Sci. U.S.A. 73, 2414–2418 (1976)PubMedCrossRefGoogle Scholar
  33. 33.
    Oppenheimer, L., Wellner, V.P., Chernov, N., Griffith, O.W.: Mapping of γ-glutamylcysteine binding site of glutathione synthetase; high specificity at the cysteine site relative to the glutamyl site. Federation Proc. 37, 848 (1978)Google Scholar
  34. 34.
    Orlowski, M., Meister, A.: The γ-Glutamyl cycle; possible transport system for amino acids. Proc. Natl. Acad. Sci. U.S.A. 67, 1248–1255 (1970)PubMedCrossRefGoogle Scholar
  35. 35.
    Orlowski, M., Meister, A.: Isolation of highly-purified γ-Glutamylcysteine synthetase from rat kidney. Biochemistry 10, 372–380 (1971)PubMedCrossRefGoogle Scholar
  36. 36.
    Orlowski, M., Meister, A.: γ-Glutamyl cyclotransferase; distribution, isozymic forms, and specificity. J. Biol. Chem. 248, 2836–2844 (1973)PubMedGoogle Scholar
  37. 37.
    Orlowski, M., Richman, P., Meister, A.: Isolation and properties of γ-L-glutamyl-cyclotransferase from human brain. Biochemistry 8, 1048–1055 (1969)PubMedCrossRefGoogle Scholar
  38. 38.
    Palekar, A.G., Tate, S.S., Meister, A.: Decrease in glutathione levels of kidney and liver after injection of methionine sulfoximine into rats. Biochem. Biophys. Res. Commun. 62, 651–657 (1975)PubMedCrossRefGoogle Scholar
  39. 39.
    Pardee, A.B.: Membrane transport proteins. Science 162, 632–637 (1968)PubMedCrossRefGoogle Scholar
  40. 40.
    Revel, J.P., Ball, E.G.: The reaction of glutathione with amino acids and related compounds as catalyzed by γ-Glutamyl transpeptidase. J. Biol. Chem. 234, 577–582 (1959)PubMedGoogle Scholar
  41. 41.
    Richards, F., Cooper, M.R., Pearce, L.A., Cowan, R.J., Spurr, C.L.: Familial spinocerebellar degeneration, hemolytic anemia, and glutathione deficiency. Arch. Int. Med. 134, 534–537 (1974)CrossRefGoogle Scholar
  42. 42.
    Richman, P., Meister, A.: Regulation of γ-glutamyl-cysteine synthetase by nonallosteric feedback inhibition by glutathione. J. Biol. Chem. 250, 1422–1426 (1975)PubMedGoogle Scholar
  43. 43.
    Richman, P.G., Orlowski, M., Meister, A.: Inhibition of γ-Glutamyleysteine synthetase by L-methionine-S-sulfoximine. J. Biol. Chem. 248, 6684–6690 (1973)PubMedGoogle Scholar
  44. 44.
    Ronzio, R.A., Meister, A.: Phosphorylation of methionine sulfoximine by glutamine synthetase. Proc. Natl. Acad. Sci. U.S.A. 59, 164–170 (1968)PubMedCrossRefGoogle Scholar
  45. 45.
    Schulman, J.D., Goodman, S.I., Mace, J.W., Patrick, A.D., Tietze, F., Butler, E.J.: Glutathionuria: inborn error of metabolism due to tissue deficiency of γ-Glutamyl transpeptidase. Biochem. Biophys. Res. Commun. 65, 68–74.(1975)PubMedCrossRefGoogle Scholar
  46. 46.
    Sekura, R., Meister, A.: Glutathione turnover in the kidney; considerations relating to the γ-Glutamyl cycle and the transport of amino acids. Proc. Natl. Acad. Sci. U.S.A. 71, 2404–2409 (1974)CrossRefGoogle Scholar
  47. 47.
    Sekura, R., Meister, A.: γ-Glutamylcysteine synthetase: further purification, “half of the sites” reactivity, subunits, and specificity. J. Biol. Chem. 252, 2599–2605 (1977)PubMedGoogle Scholar
  48. 48.
    Sekura, R., Van Der Werf, P., Meister, A.: Mechanism and significance of the mammalian pathway for elimination of D-glutamate; inhibition of glutathione synthesis by D-glutamate. Biochem. Biophys. Res. Commun. 71, 11–18 (1976)PubMedCrossRefGoogle Scholar
  49. 49.
    Taniguchi, N., Meister, A.: γ-Glutamyl cyclotransferase from rat kidney; sulfhydryl groups and isolation of a stable form of the enzyme. J. Biol. Chem. 253, 1799–1806 (1976)Google Scholar
  50. 50.
    Tate, S.S.: Interaction of γ-Glutamyl transpeptidase with S-acyl derivatives of glutathione. FEBS Lett. 54, 319–322 (1975)PubMedCrossRefGoogle Scholar
  51. 51.
    Tate, S.S., Meister, A.: Stimulation of the hydrolytic activity and decrease of the transpeptidase activity of γ-Glutamyl transpeptidase by maleate; identity of a rat kidney maleate-stimulated glutaminase and γ-Glutamyl transpeptidase. Proc. Natl. Acad. Sci. U.S.A. 71, 3329–3333 (1974)PubMedCrossRefGoogle Scholar
  52. 52.
    Tate, S.S., Meister, A.: Interaction of γ-Glutamyl transpeptidase with amino acids, dipeptides, and derivatives and analogs of glutathione. J. Biol. Chem. 249, 7593–7602 (1974)PubMedGoogle Scholar
  53. 53.
    Tate, S.S., Meister, A.: Identity of maleate-stimulated “glutaminase” with γ-glutamyl transpeptidase in rat kidney. J. Biol. Chem. 250, 4619–4624 (1975)PubMedGoogle Scholar
  54. 54.
    Tate, S.S., Meister, A.: Subunit structure and isozymic forms of γ-Glutamyl transpeptidase. Proc. Natl. Acad. Sci. U.S.A. 73, 2599–2603 (1976)PubMedCrossRefGoogle Scholar
  55. 55.
    Tate, S.S., Meister, A.: Affinity labeling of γ_glutamyl transpeptidase and location of the γ-Glutamyl binding site on the light subunit. Proc. Natl. Acad. Sci. U.S.A. 74, 931–935 (1977)PubMedCrossRefGoogle Scholar
  56. 56.
    Tate, S.S., Meister, A.: Serine-borate complex as a transition-state inhibitor of γ-Glutamyl transpeptidase. Proc. Natl. Acad. Sci. U.S.A. 75, 4806–4809 (1978)PubMedCrossRefGoogle Scholar
  57. 57.
    Tate, S.S., Ross, M.E.: Human kidney γ-Glutamyl transpeptidase. J. Biol. Chem. 252, 6042–6045 (1977)PubMedGoogle Scholar
  58. 58.
    Thompson, G.A., Meister, A.: Utilization of L-cystine by the γ-Glutamyl transpeptidase-γ-glutamyl cyclotransferase pathway. Proc. Natl. Acad. Sci. U.S.A. 72, 1985–1988 (1975)PubMedCrossRefGoogle Scholar
  59. 59.
    Thompson, G.A., Meister, A.: Hydrolysis and transfer reactions catalyzed by γ-glutamyl transpeptidase; evidence for separate substrate sites and for high affinity of L-cystine. Biochem. Biophys. Res. Commun. 71, 32–36 (1976)PubMedCrossRefGoogle Scholar
  60. 60.
    Thompson, G.A., Meister, A.: Interrelationships between the binding sites for amino acids, dipeptides, and γ-glutamyl donors in γ-glutamyl transpeptidase. J. Biol. Chem. 252, 6792–6797 (1977)PubMedGoogle Scholar
  61. 61.
    Thompson, G.A., Meister, A.: Hippurate, a possible regulator of γ-glutamyl transpeptidase. Proc. Natl. Acad. Sci. U.S.A. 76. (1979)Google Scholar
  62. 62.
    Van Der Werf, P., Griffith, O., Meister, A.: 5-oxo-prolinase (L-pyroglutamate hydrolase); purification and catalytic properties. J. Biol. Chem. 250, 6686–6692 (1975)Google Scholar
  63. 63.
    Van Der Werf, P., Orlowski, M., Meister, A.: Enzymatic conversion of 5-oxo-L-proline (L-pyrrolidone carboxylate) to L-glutamate coupled with ATP cleavage to ADP: a reaction in the γ-Glutamyl cycle. Proc. Natl. Acad. Sci. U.S.A. 68, 2982–2985 (1971)PubMedCrossRefGoogle Scholar
  64. 64.
    Van Der Werf, P., Stephani, R.A., Meister, A.: Accumulation of 5-oxoproline in mouse tissues after inhibition of 5-oxoprolinase and administration of amino acids; evidence for function of the γ-Glutamyl cycle. Proc. Natl. Acad. Sci. U.S.A. 71, 1026–1029 (1974)CrossRefGoogle Scholar
  65. 65.
    Van Der Werf, P., Meister, A.: The metabolic formation and utilization of 5-oxo-L-proline (L-pyroglutamate, L-pyrrolidone carboxylate). Adv. Enzymol. 43, 519–556 (1975)PubMedGoogle Scholar
  66. 66.
    Wellner, V.P., Sekura, R., Meister, A., Larsson, A.: Glutathione synthetase deficiency, an inborn error of metabolism involving the γ-Glutamyl cycle in patients with 5-oxoprolinuria (pyroglutamic aciduria). Proc. Natl. Acad. Sci. U.S.A. 71, 2505–2509 (1974)PubMedCrossRefGoogle Scholar
  67. 67.
    Wendel, A., Schaich, E., Weber, U., Flohé, L.: Isolierung und Molekulargewichtsbestimmung der γ-L-glutamyl-L-Cystein: Glycin-Ligase. Hoppe-Seyler’s Z. Physiol. Chem. 343, 514–522 (1972)CrossRefGoogle Scholar
  68. 68.
    Wilson, H., Cannon, R.K.: The glutamic acid-pyrrolidonecarboxylic acid system. J. Biol. Chem. 119, 309–331 (1937)Google Scholar
  69. 69.
    Woodward, G.E., Reinhart, F.E.: The effect of pH on the formation of pyrrolidone carboxylic acid and glutamic acid during enzymatic hydrolysis of glutathione by rat kidney extract. J. Biol. Chem. 145, 471–480 (1942)Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1978

Authors and Affiliations

  • A. Meister

There are no affiliations available

Personalised recommendations