Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1991 Jul 15;88(14):6303–6307. doi: 10.1073/pnas.88.14.6303

Identification of a human gamma-glutamyl cleaving enzyme related to, but distinct from, gamma-glutamyl transpeptidase.

N Heisterkamp 1, E Rajpert-De Meyts 1, L Uribe 1, H J Forman 1, J Groffen 1
PMCID: PMC52071  PMID: 1676842

Abstract

We have cloned a 2.4-kilobase cDNA from a human placental cDNA library by using a gamma-glutamyl transpeptidase [GGT; gamma-glutamyltransferase, (5-glutamyl)-peptide:amino acid 5-glutamyltransferase, EC 2.3.2.2] probe. The deduced amino acid sequence of this cDNA, GGT-rel, exhibited an overall similarity of 39.5% with human GGT. Sequences that could represent a heavy and a light chain, analogous to GGT, as well as a putative transmembrane region were identified in GGT-rel. Transfectants overexpressing GGT-rel were tested for their ability to catalyze cleavage of the gamma-glutamyl moiety from natural and synthetic substrates for GGT. Experiments with glutathione added to the medium suggested that GGT-rel could hydrolyze the gamma-glutamyl moiety. More definitive evidence was obtained in experiments in which this protein converted leukotriene C4 to leukotriene D4. However, GGT-rel did not convert synthetic substrates that are commonly used to assay GGT. Our results indicate that GGT can no longer be considered the only enzyme capable of cleaving the gamma-glutamyl linkage of leukotriene C4 and, most likely, of other natural compounds.

Full text

PDF
6303

Images in this article

6305Image
on p.6305
6305Image
on p.6305
6306Image
on p.6306

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Akerboom T. P., Sies H. Assay of glutathione, glutathione disulfide, and glutathione mixed disulfides in biological samples. Methods Enzymol. 1981;77:373–382. doi: 10.1016/s0076-6879(81)77050-2. [DOI] [PubMed] [Google Scholar]
  2. Bernström K., Orning L., Hammarström S. Gamma-Glutamyl transpeptidase, a leukotriene metabolizing enzyme. Methods Enzymol. 1982;86:38–45. doi: 10.1016/0076-6879(82)86165-x. [DOI] [PubMed] [Google Scholar]
  3. Billon M. C., Dupre G., Hanoune J. In vivo modulation of rat hepatic gamma-glutamyltransferase activity by glucocorticoids. Mol Cell Endocrinol. 1980 May;18(2):99–108. doi: 10.1016/0303-7207(80)90085-4. [DOI] [PubMed] [Google Scholar]
  4. Chen C., Okayama H. High-efficiency transformation of mammalian cells by plasmid DNA. Mol Cell Biol. 1987 Aug;7(8):2745–2752. doi: 10.1128/mcb.7.8.2745. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Coloma J., Pitot H. C. Characterization and sequence of a cDNA clone of gamma-glutamyltranspeptidase. Nucleic Acids Res. 1986 Feb 11;14(3):1393–1403. doi: 10.1093/nar/14.3.1393. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Curthoys N. P. Role of gamma-glutamyltranspeptidase in the renal metabolism of glutathione. Miner Electrolyte Metab. 1983;9(4-6):236–245. [PubMed] [Google Scholar]
  7. Fiala S., Fiala A. E., Dixon B. -Glutamyl transpeptidase in transplantable, chemically induced rat hepatomas and "spontaneous" mouse hepatomas. J Natl Cancer Inst. 1972 May;48(5):1393–1401. [PubMed] [Google Scholar]
  8. Griffiths S. A., Manson M. M. Rat liver gamma glutamyl transpeptidase mRNA differs in the 5' untranslated sequence from the corresponding kidney mRNA. Cancer Lett. 1989 Jul 1;46(1):69–74. doi: 10.1016/0304-3835(89)90217-6. [DOI] [PubMed] [Google Scholar]
  9. Hanigan M. H., Pitot H. C. Gamma-glutamyl transpeptidase--its role in hepatocarcinogenesis. Carcinogenesis. 1985 Feb;6(2):165–172. doi: 10.1093/carcin/6.2.165. [DOI] [PubMed] [Google Scholar]
  10. Heisterkamp N., Groffen J., Stephenson J. R. The human v-abl cellular homologue. J Mol Appl Genet. 1983;2(1):57–68. [PubMed] [Google Scholar]
  11. Hughey R. P., Coyle P. J., Curthoys N. P. Comparison of the association and orientation of gamma-glutamyltranspeptidase in lecithin vesicles and in native membranes. J Biol Chem. 1979 Feb 25;254(4):1124–1128. [PubMed] [Google Scholar]
  12. Kozak M. Comparison of initiation of protein synthesis in procaryotes, eucaryotes, and organelles. Microbiol Rev. 1983 Mar;47(1):1–45. doi: 10.1128/mr.47.1.1-45.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Laperche Y., Bulle F., Aissani T., Chobert M. N., Aggerbeck M., Hanoune J., Guellaën G. Molecular cloning and nucleotide sequence of rat kidney gamma-glutamyl transpeptidase cDNA. Proc Natl Acad Sci U S A. 1986 Feb;83(4):937–941. doi: 10.1073/pnas.83.4.937. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Metz S. A., Hall M. E., Harper T. W., Murphy R. C. Rapid extraction of leukotrienes from biologic fluids and quantitation by high-performance liquid chromatography. J Chromatogr. 1982 Dec 10;233:193–201. doi: 10.1016/s0378-4347(00)81746-6. [DOI] [PubMed] [Google Scholar]
  15. Morris H. R., Taylor G. W., Piper P. J., Tippins J. R. Structure of slow-reacting substance of anaphylaxis from guinea-pig lung. Nature. 1980 May 8;285(5760):104–106. doi: 10.1038/285104a0. [DOI] [PubMed] [Google Scholar]
  16. Morré D. J., Morré D. M. Preparation of mammalian plasma membranes by aqueous two-phase partition. Biotechniques. 1989 Oct;7(9):946-8, 950-4, 956-8. [PubMed] [Google Scholar]
  17. Okayama H., Berg P. A cDNA cloning vector that permits expression of cDNA inserts in mammalian cells. Mol Cell Biol. 1983 Feb;3(2):280–289. doi: 10.1128/mcb.3.2.280. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Orning L., Hammarström S., Samuelsson B. Leukotriene D: a slow reacting substance from rat basophilic leukemia cells. Proc Natl Acad Sci U S A. 1980 Apr;77(4):2014–2017. doi: 10.1073/pnas.77.4.2014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Pawlak A., Lahuna O., Bulle F., Suzuki A., Ferry N., Siegrist S., Chikhi N., Chobert M. N., Guellaen G., Laperche Y. gamma-Glutamyl transpeptidase: a single copy gene in the rat and a multigene family in the human genome. J Biol Chem. 1988 Jul 15;263(20):9913–9916. [PubMed] [Google Scholar]
  20. Pawlak A., Wu S. J., Bulle F., Suzuki A., Chikhi N., Ferry N., Baik J. H., Siegrist S., Guellaën G. Different gamma-glutamyl transpeptidase mRNAs are expressed in human liver and kidney. Biochem Biophys Res Commun. 1989 Oct 31;164(2):912–918. doi: 10.1016/0006-291x(89)91545-3. [DOI] [PubMed] [Google Scholar]
  21. Power C. A., Griffiths S. A., Simpson J. L., Laperche Y., Guellaen G., Manson M. M. Induction of gamma-glutamyl transpeptidase mRNA by aflatoxin B1 and ethoxyquin in rat liver. Carcinogenesis. 1987 May;8(5):737–740. doi: 10.1093/carcin/8.5.737. [DOI] [PubMed] [Google Scholar]
  22. Puente J., Varas M. A., Beckhaus G., Sapag-Hagar M. Gamma-glutamyltranspeptidase activity and cyclic AMP levels in rat liver and mammary gland during the lactogenic cycle and in the oestradiol-progesterone pseudo-induced pregnancy. FEBS Lett. 1979 Mar 1;99(1):215–218. doi: 10.1016/0014-5793(79)80282-3. [DOI] [PubMed] [Google Scholar]
  23. Rajpert-De Meyts E., Heisterkamp N., Groffen J. Cloning and nucleotide sequence of human gamma-glutamyl transpeptidase. Proc Natl Acad Sci U S A. 1988 Dec;85(23):8840–8844. doi: 10.1073/pnas.85.23.8840. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Samuelsson B. Leukotrienes: mediators of immediate hypersensitivity reactions and inflammation. Science. 1983 May 6;220(4597):568–575. doi: 10.1126/science.6301011. [DOI] [PubMed] [Google Scholar]
  25. Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Sawabu N., Nakagen M., Ozaki K., Wakabayashi T., Toya D., Hattori N., Ishii M. Clinical evaluation of specific gamma-GTP isoenzyme in patients with hepatocellular carcinoma. Cancer. 1983 Jan 15;51(2):327–331. doi: 10.1002/1097-0142(19830115)51:2<327::aid-cncr2820510227>3.0.co;2-c. [DOI] [PubMed] [Google Scholar]
  27. Stam K., Heisterkamp N., Reynolds F. H., Jr, Groffen J. Evidence that the phl gene encodes a 160,000-dalton phosphoprotein with associated kinase activity. Mol Cell Biol. 1987 May;7(5):1955–1960. doi: 10.1128/mcb.7.5.1955. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Stole E., Seddon A. P., Wellner D., Meister A. Identification of a highly reactive threonine residue at the active site of gamma-glutamyl transpeptidase. Proc Natl Acad Sci U S A. 1990 Mar;87(5):1706–1709. doi: 10.1073/pnas.87.5.1706. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Szasz G. A kinetic photometric method for serum gamma-glutamyl transpeptidase. Clin Chem. 1969 Feb;15(2):124–136. [PubMed] [Google Scholar]
  30. Tate S. S., Khadse V. Renal gamma-glutamyl transpeptidases: influence of glycosylation on the electrophoretic behavior and molecular weights of their subunits. Biochem Biophys Res Commun. 1986 Dec 30;141(3):1189–1194. doi: 10.1016/s0006-291x(86)80170-x. [DOI] [PubMed] [Google Scholar]
  31. Tate S. S., Meister A. gamma-Glutamyl transpeptidase: catalytic, structural and functional aspects. Mol Cell Biochem. 1981 Sep 25;39:357–368. doi: 10.1007/BF00232585. [DOI] [PubMed] [Google Scholar]
  32. Tsuji A., Matsuda Y., Katunuma N. Studies on the structure of gamma-glutamyltranspeptidase. II. Location of the segment anchoring gamma-glutamyltranspeptidase to the membrane. J Biochem. 1980 Jun;87(6):1567–1571. doi: 10.1093/oxfordjournals.jbchem.a132898. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES