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Gene Review

GGH  -  gamma-glutamyl hydrolase (conjugase,...

Homo sapiens

Synonyms: Conjugase, GH, Gamma-Glu-X carboxypeptidase, Gamma-glutamyl hydrolase
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Disease relevance of GGH


Psychiatry related information on GGH

  • The proportion of 20K hGH was significantly (P < 0.001) higher in patients with active acromegaly (9.2 +/- 2.2%; n = 33) and patients with anorexia nervosa (9.0 +/- 1.9; n = 8), both of which are characterized by chronic elevation of circulating GH levels [5].
  • Both experimental and clinical studies suggest that human GH (hGH) may have a functional role during early stages in human development [6].
  • Human GH (hGH) secretion is stimulated by vigorous physical activity, whereas immobilization reduces its release [7].
  • Thus, daily injections of GH to prepubertal short normal children is associated with development of drug dependence, followed during the abstinence period by deceleration of growth and reduction of cardiac output to levels that are lower than pretreatment values [8].
  • Rapid eye movements in REM sleep (REMs) were reduced before the therapy in one case, this decrease being reversed on hGH compensation [9].

High impact information on GGH

  • Leukemia cells that had acquired an additional chromosome containing a wild-type TPMT or GGH allele had significantly lower accumulation of thioguanine nucleotides or methotrexate polyglutamates, respectively [10].
  • Assessment of optimal GH replacement is made difficult by the apparent diverse actions of GH in health, concern about the avoidance of iatrogenic acromegaly, and the growing realization that an individual's risk of developing certain cancers may, at least in part, be influenced by cumulative exposure to the chief mediator of GH action, IGF-I [11].
  • As in all areas of clinical practice, strategies and protocols vary between centers, but most physicians experienced in the management of pituitary disease agree that GH is most appropriately begun at low doses, building up slowly to the final maintenance dose [11].
  • The proliferation rate of the two cell lines was not affected by 5-50 ng/mL hGH-RH(1-29)NH2 or 1-80 ng/mL hGH but was suppressed by 10(-6)-10(-5) M MZ-4-71 [12].
  • Effects of MZ-4-71, hGH-RH(1-29)NH2, and human GH (hGH) on cell proliferation and on the production of IGF-I and cyclic adenosine monophosphate were also evaluated in SK-ES-1 and MNNG/HOS cells in vitro [12].

Chemical compound and disease context of GGH

  • Increased GGH activity has been found in rat hepatoma cells resistant to the cancer drug methotrexate (MTX) [13].
  • Significant similarity was found between hGH and the glutamine amidotransferase type I domain of Escherichia coli carbamoyl phosphate synthetase [14].
  • Expression of the endogenous human GH (hGH) gene in response to glucocorticoids, thyroid hormone, and insulin was studied in cultures of dispersed GH-secreting human pituitary adenomas [15].
  • In 11% of untreated patients with clinical findings of acromegaly and a pathologically confirmed adenoma, IG-FBP-3 levels were elevated, although GH was suppressed to less than 2 micrograms/L with glucose [16].
  • Serum samples were obtained from 21 subjects with GH deficiency, 24 patients with acromegaly, and 56 normal subjects; 12 of whom were postmenopausal women who were studied before and during oral estrogen treatment [17].

Biological context of GGH

  • The human GH gene spans 24 kb in the human genome, with nine exons sized from 51 to 371 bp [18].
  • To clarify the specific role of GGH in determining MTX sensitivity, we investigated the phenotype produced by forced GGH overexpression in two cell types [2].
  • TPMT and GGH activities in somatic cells were concordant with germline genotypes, whereas activities in leukemia cells were determined by chromosomal number and whether the acquired chromosomes contained a wild-type or variant allele [10].
  • Furthermore, methylation of CpG1 was leukemia-cell specific and had a pronounced effect on GGH expression, whereas methylation of CpG2 was common in leukemia cells and normal leukocytes but did not significantly alter GGH expression [4].
  • These findings indicate that GGH activity in human leukemia cells is regulated by epigenetic changes, in addition to previously recognized genetic polymorphisms and karyotypic abnormalities, which collectively determine interindividual differences in GGH activity and influence MTXPG accumulation in leukemia cells [4].

Anatomical context of GGH

  • In contrast to expectations, however, GGH overexpression did not confer resistance to short MTX exposures in either cell line [2].
  • Elevated gamma-glutamyl hydrolase (GGH) activity as a contributing factor in mechanisms of acquired and intrinsic antifolate resistance has been reported for several cultured cell lines [19].
  • Within cells, MTX is metabolized to more active methotrexate polyglutamates (MTXPG), and these polyglutamates are subsequently cleaved in lysosomes by gamma-glutamyl hydrolase (GGH) [20].
  • As activity can be reliably determined using less than 5 x 10(5) eukaryotic cells, this new technique can be used to measure GGH in patient tumor samples and investigate the relationship between GGH levels and clinical MTX resistance [21].
  • These mice began to secrete hGH into saliva at puberty. hGH was detected immunocytochemically in the granulated convoluted tubular cells of the submandibular gland (SMG) [22].

Associations of GGH with chemical compounds

  • Gamma-glutamyl hydrolase (GH) plays an important role in the metabolism of folic acid and the pharmacology of antifolates such as methotrexate [18].
  • Steady-state accumulation of MTXPG seems to depend on the activity of two enzymes: folylpolyglutamate synthetase (FPGS), which adds glutamate residues, and gamma-glutamyl hydrolase (GGH), which removes them [2].
  • Gamma-glutamyl hydrolase (GGH) catalyzes degradation of the active polyglutamates of natural folates and the antifolate methotrexate (MTX) [4].
  • Using an in vitro assay screen, several glutamine antagonists [i.e., 6-diazo-5-oxo-norleucine (DON), acivicin, and azaserine] were identified as human GGH inhibitors, with DON being the most potent and displaying time-dependent inhibition [19].
  • A 55-residue protein containing the DNA binding domain of Hin recombinase, residues 139-190, with the tripeptide Gly-Gly-His (GGH) at the NH2 terminus was synthesized by stepwise solid-phase methods [23].

Other interactions of GGH

  • Kaplan-Meier survival analysis revealed that immunostaining for CPE was a statistically significant predictor of good prognosis, whereas GGH expression correlated with poor prognosis [1].
  • These 2p gains were often masked in the GGH profiles due to MYCN amplification [24].
  • These data demonstrate that polymorphisms in SLC19A1 and GGH affect polyglutamation of MTX [25].
  • In addition to the intracellular GGH, carboxypeptidase II (also called intestinal folate conjugase, prostate specific membrane antigen or N-acetyl-alpha-linked acidic dipeptidase) is another enzyme with gamma-glutamyl hydrolase activity; it resides, however, in the cellular membrane [26].
  • Overexpression, genomic amplification and therapeutic potential of inhibiting the UbcH10 ubiquitin conjugase in human carcinomas of diverse anatomic origin [27].

Analytical, diagnostic and therapeutic context of GGH

  • A rapid and sensitive procedure for the separation of methotrexate (MTX) polyglutamates2 using capillary electrophoresis (CE) is described as it applies to the in vitro assay of the enzyme gamma-glutamyl hydrolase (GGH, EC [21].
  • Until the advent of modern neuroradiological imaging techniques in 1989, a diagnosis of GH deficiency in adults carried little significance other than as a marker of hypothalamo-pituitary disease [11].
  • It is clear that the monitoring of parameters other than linear growth to help refine GH therapy should now be incorporated into childhood GH treatment protocols [11].
  • GH in plasma and urine was determined by an immunoradiometric assay, and GFR by inulin clearance [28].
  • The kidney handles GH like a microprotein involving glomerular filtration, tubular reabsorption, and urinary excretion [28].


  1. Identification of carboxypeptidase E and gamma-glutamyl hydrolase as biomarkers for pulmonary neuroendocrine tumors by cDNA microarray. He, P., Varticovski, L., Bowman, E.D., Fukuoka, J., Welsh, J.A., Miura, K., Jen, J., Gabrielson, E., Brambilla, E., Travis, W.D., Harris, C.C. Hum. Pathol. (2004) [Pubmed]
  2. Effects of overexpression of gamma-Glutamyl hydrolase on methotrexate metabolism and resistance. Cole, P.D., Kamen, B.A., Gorlick, R., Banerjee, D., Smith, A.K., Magill, E., Bertino, J.R. Cancer Res. (2001) [Pubmed]
  3. gamma-Glutamyl hydrolase and folylpolyglutamate synthetase activities predict polyglutamylation of methotrexate in acute leukemias. Longo, G.S., Gorlick, R., Tong, W.P., Lin, S., Steinherz, P., Bertino, J.R. Oncol. Res. (1997) [Pubmed]
  4. Epigenetic regulation of human gamma-glutamyl hydrolase activity in acute lymphoblastic leukemia cells. Cheng, Q., Cheng, C., Crews, K.R., Ribeiro, R.C., Pui, C.H., Relling, M.V., Evans, W.E. Am. J. Hum. Genet. (2006) [Pubmed]
  5. Serum concentration of 20K human growth hormone (20K hGH) measured by a specific enzyme-linked immunosorbent assay. Study Group of 20K hGH. Tsushima, T., Katoh, Y., Miyachi, Y., Chihara, K., Teramoto, A., Irie, M., Hashimoto, Y. J. Clin. Endocrinol. Metab. (1999) [Pubmed]
  6. Ontogeny of growth hormone receptors in human tissues: an immunohistochemical study. Simard, M., Manthos, H., Giaid, A., Lefèbvre, Y., Goodyer, C.G. J. Clin. Endocrinol. Metab. (1996) [Pubmed]
  7. Chronic baclofen therapy improves the blunted growth hormone response to intravenous arginine in subjects with spinal cord injury. Bauman, W.A., Spungen, A.M., Zhong, Y.G., Tsitouras, P.D. J. Clin. Endocrinol. Metab. (1994) [Pubmed]
  8. GH dependence and GH withdrawal syndrome in GH treatment of short normal children: evidence from growth and cardiac output. Lampit, M., Lorber, A., Vilkas, D.L., Nave, T., Hochberg, Z. Eur. J. Endocrinol. (1998) [Pubmed]
  9. Sleep disturbance in children with growth hormone deficiency. Hayashi, M., Shimohira, M., Saisho, S., Shimozawa, K., Iwakawa, Y. Brain Dev. (1992) [Pubmed]
  10. Karyotypic abnormalities create discordance of germline genotype and cancer cell phenotypes. Cheng, Q., Yang, W., Raimondi, S.C., Pui, C.H., Relling, M.V., Evans, W.E. Nat. Genet. (2005) [Pubmed]
  11. Optimizing gh therapy in adults and children. Drake, W.M., Howell, S.J., Monson, J.P., Shalet, S.M. Endocr. Rev. (2001) [Pubmed]
  12. Inhibition of growth of human osteosarcomas by antagonists of growth hormone-releasing hormone. Pinski, J., Schally, A.V., Groot, K., Halmos, G., Szepeshazi, K., Zarandi, M., Armatis, P. J. Natl. Cancer Inst. (1995) [Pubmed]
  13. Identification of single nucleotide polymorphisms in the human gamma-glutamyl hydrolase gene and characterization of promoter polymorphisms. Chave, K.J., Ryan, T.J., Chmura, S.E., Galivan, J. Gene (2003) [Pubmed]
  14. Molecular modeling and site-directed mutagenesis define the catalytic motif in human gamma -glutamyl hydrolase. Chave, K.J., Auger, I.E., Galivan, J., Ryan, T.J. J. Biol. Chem. (2000) [Pubmed]
  15. Hormonal regulation of expression of the endogenous and transfected human growth hormone gene. Isaacs, R.E., Findell, P.R., Mellon, P., Wilson, C.B., Baxter, J.D. Mol. Endocrinol. (1987) [Pubmed]
  16. Serum insulin-like growth factor-binding protein-3 levels in the diagnosis of acromegaly. Grinspoon, S., Clemmons, D., Swearingen, B., Klibanski, A. J. Clin. Endocrinol. Metab. (1995) [Pubmed]
  17. Direct quantitation of growth hormone binding protein in human serum by a ligand immunofunctional assay: comparison with immunoprecipitation and chromatographic methods. Rajkovic, I.A., Valiontis, E., Ho, K.K. J. Clin. Endocrinol. Metab. (1994) [Pubmed]
  18. Structural organization of the human gamma-glutamyl hydrolase gene. Yin, D., Chave, K.J., Macaluso, C.R., Galivan, J., Yao, R. Gene (1999) [Pubmed]
  19. gamma-Glutamyl hydrolase from human sarcoma HT-1080 cells: characterization and inhibition by glutamine antagonists. Waltham, M.C., Li, W.W., Gritsman, H., Tong, W.P., Bertino, J.R. Mol. Pharmacol. (1997) [Pubmed]
  20. Methotrexate intracellular disposition in acute lymphoblastic leukemia: a mathematical model of gamma-glutamyl hydrolase activity. Panetta, J.C., Wall, A., Pui, C.H., Relling, M.V., Evans, W.E. Clin. Cancer Res. (2002) [Pubmed]
  21. Capillary electrophoresis of methotrexate polyglutamates and its application in evaluation of gamma-glutamyl hydrolase activity. Waltham, M.C., Lin, S., Li, W.W., Göker, E., Gritsman, H., Tong, W.P., Bertino, J.R. J. Chromatogr. B Biomed. Sci. Appl. (1997) [Pubmed]
  22. Cell-specific and developmental regulation of a nerve growth factor-human growth hormone fusion gene in transgenic mice. Alexander, J.M., Hsu, D., Penchuk, L., Heinrich, G. Neuron (1989) [Pubmed]
  23. Sequence-specific oxidative cleavage of DNA by a designed metalloprotein, Ni(II).GGH(Hin139-190). Mack, D.P., Dervan, P.B. Biochemistry (1992) [Pubmed]
  24. Combined M-FISH and CGH analysis allows comprehensive description of genetic alterations in neuroblastoma cell lines. Van Roy, N., Van Limbergen, H., Vandesompele, J., Van Gele, M., Poppe, B., Salwen, H., Laureys, G., Manoel, N., De Paepe, A., Speleman, F. Genes Chromosomes Cancer (2001) [Pubmed]
  25. Contribution of common polymorphisms in reduced folate carrier and gamma-glutamylhydrolase to methotrexate polyglutamate levels in patients with rheumatoid arthritis. Dervieux, T., Kremer, J., Lein, D.O., Capps, R., Barham, R., Meyer, G., Smith, K., Caldwell, J., Furst, D.E. Pharmacogenetics (2004) [Pubmed]
  26. Gamma-glutamyl hydrolase and drug resistance. Schneider, E., Ryan, T.J. Clin. Chim. Acta (2006) [Pubmed]
  27. Overexpression, genomic amplification and therapeutic potential of inhibiting the UbcH10 ubiquitin conjugase in human carcinomas of diverse anatomic origin. Wagner, K.W., Sapinoso, L.M., El-Rifai, W., Frierson, H.F., Butz, N., Mestan, J., Hofmann, F., Deveraux, Q.L., Hampton, G.M. Oncogene (2004) [Pubmed]
  28. Metabolic clearance of recombinant human growth hormone in health and chronic renal failure. Haffner, D., Schaefer, F., Girard, J., Ritz, E., Mehls, O. J. Clin. Invest. (1994) [Pubmed]
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