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Gene Review

Ggt1  -  gamma-glutamyltransferase 1

Mus musculus

Synonyms: AI746379, CD224, GGT, GGT 1, GGT-1, ...
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Disease relevance of Ggt1

  • The disposition and toxicity of methylmercury, a ubiquitous environmental pollutant, is modulated by binding to the endogenous tripeptide glutathione (GSH) and metabolism of the resulting methylmercury-glutathione complex by the ectoproteins gamma-glutamyl transpeptidase (GGT) and dipeptidase [1].
  • Mice deficient in gamma-glutamyl transpeptidase (GGT) are growth retarded as a result of cysteine deficiency secondary to excessive glutathione excretion in urine and display coat color defects and cataracts [2].
  • In addition, analysis of vertebrae and tibiae of GGT-/- mice revealed a severe osteopenia [3].
  • Later (after 20-30 wk), focal areas of gamma-glutamyl transpeptidase (GGT) activity appeared in a few papillomas, whereas TGFbeta1 expression began to decrease [4].
  • gamma-Glutamyltransferase (GGT), an enzyme not found in normal adult epidermis, was detected in most skin papillomas larger than 13 mm in diameter and in all squamous carcinomas induced by 7,12-dimethylbenz[a]anthracene initiation and 12-O-tetradecanoylphorbol 13-acetate promotion in noninbred Sencar mice [5].

High impact information on Ggt1


Chemical compound and disease context of Ggt1

  • Metastasis (number of foci/100 mm(3) of liver) increased in B16MF1 cells pretreated with GSH ester ( approximately 3-fold, P <.01), and decreased in B16MF1/Tet-GGT and B16MF10 cells pretreated with the GSH synthesis inhibitor L-buthionine (S,R)-sulphoximine ( approximately 5-fold and 2-fold, respectively, P <.01) [9].
  • These data suggest that renal cisplatin toxicity is dependent on GGT activity, and is not correlated with uptake [10].
  • At 1 month, lungs from bleomycin-treated GGT-/- mice exhibited minimal areas of fibrosis compared with wild-type mice(light microscopy fibrosis index: 510 +/- 756 versus 1975 +/- 817, p < 0.01) [11].
  • Pretreatment with the anionic transport inhibitor probenecid by i.p., (0.75 mmol/kg, 30 min prior to and 10 min and 5 h following DCE administration) and with the gamma-glutamyltranspeptidase (GGT) inactivator acivicin by gavage and i.p. (50 mg/kg, 1 h and 30 min prior to DCE administration) failed to prevent DCE-induced renal toxicity [12].
  • Administering ethanol (6.32 g/kg body weight p.o.) to 4-week-old healthy mice for 45 days resulted in significantly elevated levels of plasma leptin, total bilirubin, gamma-glutamyl transpeptidase (GGT), tissue lipid hydroperoxides (LOOH), and lowered levels of tissue vitamins C and E when compared with those of the control mice [13].

Biological context of Ggt1

  • These findings demonstrate the importance of GGT and the gamma-glutamyl cycle in cysteine and GSH homeostasis [14].
  • Thus, GGT(-/-) mice exhibit a loss of GSH homeostasis and impaired oxidative phosphorylation, which may be related to the rate of adenosine triphosphate (ATP) formation and subsequently leads to progressive liver injury, which characterizes the diseased state [15].
  • These findings provide direct evidence for a major role of GGT in regulating the tissue distribution and elimination of methylmercury and inorganic mercury and provide additional support for the use of NAC as an antidote in methylmercury poisoning [1].
  • Here, we present an analysis of the reproductive phenotypes of GGT-deficient mice [2].
  • Gamma-Glutamyltranspeptidase (GGT) catalyzes the first step in the extracellular hydrolysis of glutathione (GSH) and plays a critical role in GSH recycling; however, little is known about the impact of diminished GGT activity on immune function [16].

Anatomical context of Ggt1

  • To learn more about the role of GGT in metabolism in vivo, we used embryonic stem cell technology to generate GGT-deficient (GGTm1/GGTm1) mice [14].
  • Mitochondrial adenine nucleotide content was decreased by >/=40% in mitochondria obtained from GGT(-/-) mice [15].
  • Respiratory control ratios (RCRs) of GGT(-/-) mice liver mitochondria were </=60% those of wild-type mice primarily as a result of impaired state 3 respiration [15].
  • Furthermore, both native GGT and inactive GGT stimulated the expression of the receptor activator of nuclear factor-kappaB ligand (RANKL) mRNA and protein from bone marrow stromal cells [17].
  • An antibody against GGT inhibited osteoclast formation but not the enzymatic activity [17].

Associations of Ggt1 with chemical compounds

  • Membrane-bound dipeptidase (MBD) participates in the degradation of glutathione by cleaving the cysteinyl-glycine bond of cystinyl bisglycine (oxidized cysteinyl-glycine) following removal of a gamma-glutamyl group by gamma-glutamyl transpeptidase (GGT) [18].
  • We also found that supplementation of GGT(-/-) mice with N-acetylcysteine (NAC) partially restored liver GSH, but fully restored mitochondrial GSH and respiratory function [15].
  • Pretreatment of primary mouse epidermal cell cultures with chymostatin, a protease inhibitor, blocked the increase in transglutaminase (R-glutaminyl-peptide:amine gamma-glutamyltransferase, EC activity resulting from treatment with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) or with retinoic acid [19].
  • The activity is membrane-bound and is inhibited by acivicin, a known inhibitor of GGT [20].
  • Wild-type and heterozygous mice excreted from 11 to 24% of the dose in the first 48 hours, whereas the GGT-deficient mice excreted 55 to 66% of the dose, with most of the methylmercury being excreted in urine [1].

Other interactions of Ggt1

  • However, in the lung, MBD is expressed at high levels, whereas GGT is almost undetectable [18].
  • Here we show that in vivo GGL, and not GGT as previously believed, is primarily responsible for conversion of leukotriene C(4) to leukotriene D(4), the most potent of the cysteinyl leukotrienes and the immediate precursor of leukotriene E(4) [21].
  • On the other hand, almost all SCCs showed suprabasal staining for alpha6beta4 and widespread cyclin D1 and K13 expression, whereas only about half showed positive focal staining for GGT activity [4].
  • Relative liver, heart, and spleen weights were affected by handling of DEX-E. coli-treated birds, as were serum chemistry values for calcium, iron, glucose, total protein, blood urea nitogen, uric acid, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and gamma-glutamyltransferase [22].
  • LTC4-converting activity has a tissue distribution different from GGT with highest activity in spleen followed by small intestine, kidney, and pancreas and lower activity in liver and lung [20].

Analytical, diagnostic and therapeutic context of Ggt1


  1. Accelerated methylmercury elimination in gamma-glutamyl transpeptidase-deficient mice. Ballatori, N., Wang, W., Lieberman, M.W. Am. J. Pathol. (1998) [Pubmed]
  2. Reproductive defects in gamma-glutamyl transpeptidase-deficient mice. Kumar, T.R., Wiseman, A.L., Kala, G., Kala, S.V., Matzuk, M.M., Lieberman, M.W. Endocrinology (2000) [Pubmed]
  3. Reversible skeletal abnormalities in gamma-glutamyl transpeptidase-deficient mice. Levasseur, R., Barrios, R., Elefteriou, F., Glass, D.A., Lieberman, M.W., Karsenty, G. Endocrinology (2003) [Pubmed]
  4. Changes in protein expression during multistage mouse skin carcinogenesis. Rundhaug, J.E., Gimenez-Conti, I., Stern, M.C., Budunova, I.V., Kiguchi, K., Bol, D.K., Coghlan, L.G., Conti, C.J., DiGiovanni, J., Fischer, S.M., Winberg, L.D., Slaga, T.J. Mol. Carcinog. (1997) [Pubmed]
  5. Simultaneous appearance of keratin modifications and gamma-glutamyltransferase activity as indicators of tumor progression in mouse skin papillomas. Klein-Szanto, A.J., Nelson, K.G., Shah, Y., Slaga, T.J. J. Natl. Cancer Inst. (1983) [Pubmed]
  6. Secretion of a lambda 2 immunoglobulin chain is prevented by a single amino acid substitution in its variable region. Wu, G.E., Hozumi, N., Murialdo, H. Cell (1983) [Pubmed]
  7. Dimethyl sulfoxide-induced transglutaminase activity in murine-derived Friend erythroleukemia cells. Hsu, K.H., Friedman, H. J. Natl. Cancer Inst. (1983) [Pubmed]
  8. Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis. de Vree, J.M., Jacquemin, E., Sturm, E., Cresteil, D., Bosma, P.J., Aten, J., Deleuze, J.F., Desrochers, M., Burdelski, M., Bernard, O., Oude Elferink, R.P., Hadchouel, M. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  9. gamma-Glutamyl transpeptidase overexpression increases metastatic growth of B16 melanoma cells in the mouse liver. Obrador, E., Carretero, J., Ortega, A., Medina, I., Rodilla, V., Pellicer, J.A., Estrela, J.M. Hepatology (2002) [Pubmed]
  10. Gamma-glutamyl transpeptidase-deficient mice are resistant to the nephrotoxic effects of cisplatin. Hanigan, M.H., Lykissa, E.D., Townsend, D.M., Ou, C.N., Barrios, R., Lieberman, M.W. Am. J. Pathol. (2001) [Pubmed]
  11. Bleomycin-induced pulmonary fibrosis is attenuated in gamma-glutamyl transpeptidase-deficient mice. Pardo, A., Ruiz, V., Arreola, J.L., Ramírez, R., Cisneros-Lira, J., Gaxiola, M., Barrios, R., Kala, S.V., Lieberman, M.W., Selman, M. Am. J. Respir. Crit. Care Med. (2003) [Pubmed]
  12. Nephrotoxicity mechanism of 1,1-dichloroethylene in mice. Ban, M., Hettich, D., Huguet, N., Cavelier, L. Toxicol. Lett. (1995) [Pubmed]
  13. Effect of hyperleptinaemia on chronic ethanol-induced hepatotoxicity in mice. Balasubramaniyan, V., Nalini, N. Fundamental & clinical pharmacology. (2006) [Pubmed]
  14. Growth retardation and cysteine deficiency in gamma-glutamyl transpeptidase-deficient mice. Lieberman, M.W., Wiseman, A.L., Shi, Z.Z., Carter, B.Z., Barrios, R., Ou, C.N., Chévez-Barrios, P., Wang, Y., Habib, G.M., Goodman, J.C., Huang, S.L., Lebovitz, R.M., Matzuk, M.M. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  15. gamma-glutamyltranspeptidase-deficient knockout mice as a model to study the relationship between glutathione status, mitochondrial function, and cellular function. Will, Y., Fischer, K.A., Horton, R.A., Kaetzel, R.S., Brown, M.K., Hedstrom, O., Lieberman, M.W., Reed, D.J. Hepatology (2000) [Pubmed]
  16. Gamma-glutamyltranspeptidase knockout mice as a model for understanding the consequences of diminished glutathione on T cell-dependent immune responses. Lawrence, B.P., Will, Y., Reed, D.J., Kerkvliet, N.I. Eur. J. Immunol. (2000) [Pubmed]
  17. Gamma-glutamyltranspeptidase stimulates receptor activator of nuclear factor-kappaB ligand expression independent of its enzymatic activity and serves as a pathological bone-resorbing factor. Niida, S., Kawahara, M., Ishizuka, Y., Ikeda, Y., Kondo, T., Hibi, T., Suzuki, Y., Ikeda, K., Taniguchi, N. J. Biol. Chem. (2004) [Pubmed]
  18. Four distinct membrane-bound dipeptidase RNAs are differentially expressed and show discordant regulation with gamma-glutamyl transpeptidase. Habib, G.M., Barrios, R., Shi, Z.Z., Lieberman, M.W. J. Biol. Chem. (1996) [Pubmed]
  19. Inhibition of 12-O-tetradecanoylphorbol-13-acetate induction of epidermal transglutaminase activity by protease inhibitors. Kawamura, H., Strickland, J.E., Yuspa, S.H. Cancer Res. (1983) [Pubmed]
  20. Metabolism of leukotriene C4 in gamma-glutamyl transpeptidase-deficient mice. Carter, B.Z., Wiseman, A.L., Orkiszewski, R., Ballard, K.D., Ou, C.N., Lieberman, M.W. J. Biol. Chem. (1997) [Pubmed]
  21. Gamma-glutamyl leukotrienase, a novel endothelial membrane protein, is specifically responsible for leukotriene D(4) formation in vivo. Han, B., Luo, G., Shi, Z.Z., Barrios, R., Atwood, D., Liu, W., Habib, G.M., Sifers, R.N., Corry, D.B., Lieberman, M.W. Am. J. Pathol. (2002) [Pubmed]
  22. Effect of early handling of turkey poults on later responses to a dexamethasone-Escherichia coli challenge. 1. Production values and physiological response. Huff, G.R., Huff, W.E., Balog, J.M., Rath, N.C. Poult. Sci. (2001) [Pubmed]
  23. Mapping of human gamma-glutamyl transpeptidase genes on chromosome 22 and other human autosomes. Figlewicz, D.A., Delattre, O., Guellaen, G., Krizus, A., Thomas, G., Zucman, J., Rouleau, G.A. Genomics (1993) [Pubmed]
  24. gamma-Glutamyl transferase (GGT) deficiency in the GGTenu1 mouse results from a single point mutation that leads to a stop codon in the first coding exon of GGT mRNA. Jean, J.C., Harding, C.O., Oakes, S.M., Yu, Q., Held, P.K., Joyce-Brady, M. Mutagenesis (1999) [Pubmed]
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