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Gene Review

GATM  -  glycine amidinotransferase (L...

Homo sapiens

Synonyms: AGAT, AT, CCDS3, Glycine amidinotransferase, mitochondrial, L-arginine:glycine amidinotransferase, ...
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Disease relevance of GATM

  • This Phase II trial was designed to assess the efficacy of a strategy designed to modulate the resistance to carmustine (BCNU) mediated by AGAT using streptozocin (STZ) in patients with advanced refractory melanoma [1].
  • New strategies designed to deplete AGAT activity using O6-benzylguanine or temozolomide should be explored with careful attention to the possibility that this approach may potentiate both the toxicity and efficacy of BCNU [1].
  • There was no significant difference between levels of AGAT activity in lung cancer and noncancer patients [2].
  • On the continuous 21-day schedule, AGAT inactivation was significantly greater in patients who experienced severe thrombocytopenia than those who did not (90.3+/-5.5 vs 72.5+/-16.1%, P<0.045) [3].
  • These mice revealed decreased weight gain and reduced life expectancy, disturbed fat metabolism, behavioral abnormalities and impaired learning capacity.Oral creatine supplementation improved the clinical symptoms in both AGAT and GAMT deficiency, but not in creatine transporter deficiency [4].

Psychiatry related information on GATM


High impact information on GATM

  • In contrast, treatment with BCNU plus O6-methylguanine or streptozocin did not produce growth delays substantially different from those produced by BCNU alone, reflecting the more efficient depletion of AGAT by O6-benzylguanine [6].
  • Resistance to nitrosoureas and methylating agents, which damage DNA, can be mediated by a DNA repair protein, O6-alkylguanine-DNA alkyltransferase (AGAT) [6].
  • RESULTS: Pretreatment with O6-benzylguanine, O6-methylguanine, or streptozocin reduced AGAT activity to 4%, 25%, and 95% of control values, respectively, in D341 Med and 0%, 0%, and 25% of control values, respectively, in D-456 MG 1 hour after injection [6].
  • We administered intravenous arginine to six patients and six controls to study in vivo inhibition by high ornithine concentrations of arginine-glycine transamidinase, the rate-limiting enzyme in creatine synthesis [7].
  • Arginine:glycine amidinotransferase (AGAT) catalyzes the first step of creatine synthesis, resulting in the formation of guanidinoacetate, which is a substrate for creatine formation [5].

Chemical compound and disease context of GATM

  • The differential contribution of arginase and transamidinase to ornithine biosynthesis in two achromic human melanoma cell lines [8].
  • Therefore, O6BG i.a., by virtue of rapid AGAT depletion and selective uptake into i.c. tumors, offers significant potential for regional chemomodulation of AGAT-mediated nitrosourea resistance in malignant human gliomas with concomitant reduction of systemic toxicity [9].
  • We evaluated the influence of AGAT activity inhibition by BNAG on the ability of two CENUs, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and 3-(2-chloroethyl)-1-(2-methylsulphonyl)ethyl-3-nitrosourea (cystemustine), to induce an apoptotic response in two melanoma cell lines, M3 Dau (Mer ) and IPC 227F (Mer ) [10].

Biological context of GATM


Anatomical context of GATM


Associations of GATM with chemical compounds


Other interactions of GATM


Analytical, diagnostic and therapeutic context of GATM


  1. Carmustine and streptozocin in refractory melanoma: an attempt at modulation of O-alkylguanine-DNA-alkyltransferase. Smith, D.C., Gerson, S.L., Liu, L., Donnelly, S., Day, R., Trump, D.L., Kirkwood, J.M. Clin. Cancer Res. (1996) [Pubmed]
  2. Smoking-related increase in O6-alkylguanine-DNA alkyltransferase activity in human lung tissue. Drin, I., Schoket, B., Kostic, S., Vincze, I. Carcinogenesis (1994) [Pubmed]
  3. Marked inactivation of O6-alkylguanine-DNA alkyltransferase activity with protracted temozolomide schedules. Tolcher, A.W., Gerson, S.L., Denis, L., Geyer, C., Hammond, L.A., Patnaik, A., Goetz, A.D., Schwartz, G., Edwards, T., Reyderman, L., Statkevich, P., Cutler, D.L., Rowinsky, E.K. Br. J. Cancer (2003) [Pubmed]
  4. Health implications of creatine: can oral creatine supplementation protect against neurological and atherosclerotic disease? Wyss, M., Schulze, A. Neuroscience (2002) [Pubmed]
  5. Arginine:glycine amidinotransferase deficiency: the third inborn error of creatine metabolism in humans. Item, C.B., Stöckler-Ipsiroglu, S., Stromberger, C., Mühl, A., Alessandrì, M.G., Bianchi, M.C., Tosetti, M., Fornai, F., Cioni, G. Am. J. Hum. Genet. (2001) [Pubmed]
  6. Enhancement of nitrosourea activity in medulloblastoma and glioblastoma multiforme. Friedman, H.S., Dolan, M.E., Moschel, R.C., Pegg, A.E., Felker, G.M., Rich, J., Bigner, D.D., Schold, S.C. J. Natl. Cancer Inst. (1992) [Pubmed]
  7. Gyrate atrophy of the choroid and retina with hyperornithinemia. Deficient formation of guanidinoacetic acid from arginine. Sipilä, I., Simell, O., Arjomaa, P. J. Clin. Invest. (1980) [Pubmed]
  8. The differential contribution of arginase and transamidinase to ornithine biosynthesis in two achromic human melanoma cell lines. Thomasset, N., Quash, G.A., Doré, J.F. FEBS Lett. (1982) [Pubmed]
  9. Intraarterial O6-benzylguanine enables the specific therapy of nitrosourea-resistant intracranial human glioma xenografts in athymic rats with 1,3-bis(2-chloroethyl)-1-nitrosourea. Kurpad, S.N., Dolan, M.E., McLendon, R.E., Archer, G.E., Moschel, R.C., Pegg, A.E., Bigner, D.D., Friedman, H.S. Cancer Chemother. Pharmacol. (1997) [Pubmed]
  10. Inhibition of O6-alkylguanine-DNA alkyltransferase by O6-benzyl-N2-acetylguanosine increases chloroethylnitrosourea-induced apoptosis in Mer+ human melanoma cells. Debiton, E., Glasser, A.L., Marchenay, C., Rolhion, C., Maurizis, J.C., Madelmont, J.C. Melanoma Res. (2002) [Pubmed]
  11. Recombinant expression and isolation of human L-arginine:glycine amidinotransferase and identification of its active-site cysteine residue. Humm, A., Fritsche, E., Mann, K., Göhl, M., Huber, R. Biochem. J. (1997) [Pubmed]
  12. The amino acid sequences of human and pig L-arginine:glycine amidinotransferase. Humm, A., Huber, R., Mann, K. FEBS Lett. (1994) [Pubmed]
  13. A randomized phase I and pharmacological trial of sequences of 1,3-bis(2-chloroethyl)-1-nitrosourea and temozolomide in patients with advanced solid neoplasms. Hammond, L.A., Eckardt, J.R., Kuhn, J.G., Gerson, S.L., Johnson, T., Smith, L., Drengler, R.L., Campbell, E., Weiss, G.R., Von Hoff, D.D., Rowinsky, E.K. Clin. Cancer Res. (2004) [Pubmed]
  14. Temozolomide 3 weeks on and 1 week off as first-line therapy for recurrent glioblastoma: phase II study from gruppo italiano cooperativo di neuro-oncologia (GICNO). Brandes, A.A., Tosoni, A., Cavallo, G., Bertorelle, R., Gioia, V., Franceschi, E., Biscuola, M., Blatt, V., Crin??, L., Ermani, M. Br. J. Cancer (2006) [Pubmed]
  15. Evidence for creatine biosynthesis in Müller glia. Nakashima, T., Tomi, M., Tachikawa, M., Watanabe, M., Terasaki, T., Hosoya, K. Glia (2005) [Pubmed]
  16. Renal arginine metabolism. Brosnan, M.E., Brosnan, J.T. J. Nutr. (2004) [Pubmed]
  17. Clinical characteristics and diagnostic clues in inborn errors of creatine metabolism. Stromberger, C., Bodamer, O.A., Stöckler-Ipsiroglu, S. J. Inherit. Metab. Dis. (2003) [Pubmed]
  18. Crystal structure and mechanism of human L-arginine:glycine amidinotransferase: a mitochondrial enzyme involved in creatine biosynthesis. Humm, A., Fritsche, E., Steinbacher, S., Huber, R. EMBO J. (1997) [Pubmed]
  19. The ligand-induced structural changes of human L-Arginine:Glycine amidinotransferase. A mutational and crystallographic study. Fritsche, E., Humm, A., Huber, R. J. Biol. Chem. (1999) [Pubmed]
  20. First-line chemotherapy with cisplatin plus fractionated temozolomide in recurrent glioblastoma multiforme: a phase II study of the Gruppo Italiano Cooperativo di Neuro-Oncologia. Brandes, A.A., Basso, U., Reni, M., Vastola, F., Tosoni, A., Cavallo, G., Scopece, L., Ferreri, A.J., Panucci, M.G., Monfardini, S., Ermani, M. J. Clin. Oncol. (2004) [Pubmed]
  21. The effect of growth hormone and thyroxine on the amount of L-arginine:glycine amidinotransferase in kidneys of hypophysectomized rats. Purification and some properties of rat kidney transamidinase. McGuire, D.M., Tormanen, C.D., Segal, I.S., Van Pilsum, J.F. J. Biol. Chem. (1980) [Pubmed]
  22. Estrogen modulates the expression of L-arginine:glycine amidinotransferase in chick liver. Zhu, Y., Evans, M.I. Mol. Cell. Biochem. (2001) [Pubmed]
  23. Partial purification and properties of a transamidinase from Lathyrus sativus seedlings. Involvement in homoarginine metabolism and amine interconversions. Srivenugopal, K.S., Adiga, P.R. Biochem. J. (1980) [Pubmed]
  24. Guanidinoacetate and creatine plus creatinine assessment in physiologic fluids: an effective diagnostic tool for the biochemical diagnosis of arginine:glycine amidinotransferase and guanidinoacetate methyltransferase deficiencies. Carducci, C., Birarelli, M., Leuzzi, V., Carducci, C., Battini, R., Cioni, G., Antonozzi, I. Clin. Chem. (2002) [Pubmed]
  25. Substrate binding and catalysis by L-arginine:glycine amidinotransferase--a mutagenesis and crystallographic study. Fritsche, E., Humm, A., Huber, R. Eur. J. Biochem. (1997) [Pubmed]
  26. The purification and characterization of human kidney L-arginine:glycine amidinotransferase. Gross, M.D., Eggen, M.A., Simon, A.M., Van Pilsum, J.F. Arch. Biochem. Biophys. (1986) [Pubmed]
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