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Gene Review

GLUD1  -  glutamate dehydrogenase 1

Homo sapiens

Synonyms: GDH, GDH 1, GDH1, GLUD, Glutamate dehydrogenase 1, mitochondrial
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Disease relevance of GLUD1

  • GLUD1 mutations were found in all patients with hyperammonemia [1].
  • We then started therapy against hyperammonaemia with little effect and, at the age of 15 years, we analysed the GLUD1 gene and found a previously reported gain-of-function mutation in the gene, resulting in a change of her diagnosis to hyperinsulinism/hyperammonaemia (HI/HA) syndrome [2].
  • Because blindness due to neuroretinal degeneration can occur in rare forms of multiple system atrophy, we searched for retina-specific GLUD mRNA(s) by screening a lambda gt10 library derived from human retina [3].
  • Using PCR/single-strand conformation polymorphism analysis of the gene encoding GDH in 12 Japanese patients with persistent hyperinsulinemic hypoglycemia of infancy (PHHI), we found a mutation (Y266C) in one PHHI patient [4].
  • The effect of the unregulated increase in GDH activity on insulin secretion was examined by overexpressing GDH266C in an insulinoma cell line, MIN6 [4].

Psychiatry related information on GLUD1


High impact information on GLUD1

  • SIRT4 Inhibits Glutamate Dehydrogenase and Opposes the Effects of Calorie Restriction in Pancreatic beta Cells [10].
  • GDH is known to promote the metabolism of glutamate and glutamine, generating ATP, which promotes insulin secretion [10].
  • These results indicate that SIRT4 functions in beta cell mitochondria to repress the activity of GDH by ADP-ribosylation, thereby downregulating insulin secretion in response to amino acids, effects that are alleviated during CR [10].
  • Furthermore, GDH from SIRT4-deficient or CR mice is insensitive to phosphodiesterase, an enzyme that cleaves ADP-ribose, suggesting the absence of ADP-ribosylation [10].
  • Loss of SIRT4 in insulinoma cells activates GDH, thereby upregulating amino acid-stimulated insulin secretion [10].

Chemical compound and disease context of GLUD1


Biological context of GLUD1


Anatomical context of GLUD1

  • Our results directly illustrate the importance of GDH in the regulation of insulin secretion from pancreatic beta-cells [4].
  • The activity of the mutant GDH (GDH266C), expressed in COS-7 cells, was constitutively elevated, and allosteric regulations by ADP and GTP were severely impaired [4].
  • Glutamate dehydrogenase (GLUD) is a key metabolic enzyme of the mitochondrion, playing an important role in mammalian neuronal transmission [19].
  • GTP exerts a powerful inhibitory effect (IC(50) = 0.20 mM) on the housekeeping GDH; in contrast, the nerve tissue isoenzyme is resistant to GTP inhibition [20].
  • In mammalian brain, GDH is located predominantly in astrocytes, where it is probably involved in the metabolism of transmitter glutamate [20].

Associations of GLUD1 with chemical compounds


Physical interactions of GLUD1


Enzymatic interactions of GLUD1


Regulatory relationships of GLUD1


Other interactions of GLUD1


Analytical, diagnostic and therapeutic context of GLUD1


  1. Facial appearance in persistent hyperinsulinemic hypoglycemia. de Lonlay, P., Cormier-Daire, V., Amiel, J., Touati, G., Goldenberg, A., Fournet, J.C., Brunelle, F., Nihoul-Fékété, C., Rahier, J., Junien, C., Robert, J.J., Saudubray, J.M. Am. J. Med. Genet. (2002) [Pubmed]
  2. A case of hyperinsulinism/hyperammonaemia syndrome with reduced carbamoyl-phosphate synthetase-1 activity in liver: a pitfall in enzymatic diagnosis for hyperammonaemia. Ihara, K., Miyako, K., Ishimura, M., Kuromaru, R., Wang, H.Y., Yasuda, K., Hara, T. J. Inherit. Metab. Dis. (2005) [Pubmed]
  3. Novel human glutamate dehydrogenase expressed in neural and testicular tissues and encoded by an X-linked intronless gene. Shashidharan, P., Michaelidis, T.M., Robakis, N.K., Kresovali, A., Papamatheakis, J., Plaitakis, A. J. Biol. Chem. (1994) [Pubmed]
  4. Unregulated elevation of glutamate dehydrogenase activity induces glutamine-stimulated insulin secretion: identification and characterization of a GLUD1 gene mutation and insulin secretion studies with MIN6 cells overexpressing the mutant glutamate dehydrogenase. Tanizawa, Y., Nakai, K., Sasaki, T., Anno, T., Ohta, Y., Inoue, H., Matsuo, K., Koga, M., Furukawa, S., Oka, Y. Diabetes (2002) [Pubmed]
  5. Single amino acid substitution (G456A) in the vicinity of the GTP binding domain of human housekeeping glutamate dehydrogenase markedly attenuates GTP inhibition and abolishes the cooperative behavior of the enzyme. Zaganas, I., Plaitakis, A. J. Biol. Chem. (2002) [Pubmed]
  6. Serum desialotransferrin in the detection of alcohol abuse. Definition of a Tf index. Schellenberg, F., Weill, J. Drug and alcohol dependence. (1987) [Pubmed]
  7. Lymphocyte glutamate dehydrogenase activity in normal aging and neurological diseases. Iwatsuji, K., Nakamura, S., Kameyama, M. Gerontology. (1989) [Pubmed]
  8. Serum glutamate dehydrogenase is not a reliable marker of liver cell necrosis in alcoholics. Jenkins, W.J., Rosalki, S.B., Foo, Y., Scheuer, P.J., Nemesanszky, E., Sherlock, S. J. Clin. Pathol. (1982) [Pubmed]
  9. ATP production rate in mitochondria isolated from microsamples of human muscle. Wibom, R., Hultman, E. Am. J. Physiol. (1990) [Pubmed]
  10. SIRT4 Inhibits Glutamate Dehydrogenase and Opposes the Effects of Calorie Restriction in Pancreatic beta Cells. Haigis, M.C., Mostoslavsky, R., Haigis, K.M., Fahie, K., Christodoulou, D.C., Murphy, A.J., Valenzuela, D.M., Yancopoulos, G.D., Karow, M., Blander, G., Wolberger, C., Prolla, T.A., Weindruch, R., Alt, F.W., Guarente, L. Cell (2006) [Pubmed]
  11. Familial leucine-sensitive hypoglycemia of infancy due to a dominant mutation of the beta-cell sulfonylurea receptor. Magge, S.N., Shyng, S.L., MacMullen, C., Steinkrauss, L., Ganguly, A., Katz, L.E., Stanley, C.A. J. Clin. Endocrinol. Metab. (2004) [Pubmed]
  12. Abnormal platelet glutamate dehydrogenase activity and activation in dominant and nondominant olivopontocerebellar atrophy. Sorbi, S., Tonini, S., Giannini, E., Piacentini, S., Marini, P., Amaducci, L. Ann. Neurol. (1986) [Pubmed]
  13. Importance of glutamate 279 for the coenzyme binding of human glutamate dehydrogenase. Yoon, H.Y., Cho, E.H., Kwon, H.Y., Choi, S.Y., Cho, S.W. J. Biol. Chem. (2002) [Pubmed]
  14. Hyperinsulinism/hyperammonemia syndrome in children with regulatory mutations in the inhibitory guanosine triphosphate-binding domain of glutamate dehydrogenase. MacMullen, C., Fang, J., Hsu, B.Y., Kelly, A., de Lonlay-Debeney, P., Saudubray, J.M., Ganguly, A., Smith, T.J., Stanley, C.A. J. Clin. Endocrinol. Metab. (2001) [Pubmed]
  15. Hyperinsulinism and hyperammonemia syndrome: report of twelve unrelated patients. De Lonlay, P., Benelli, C., Fouque, F., Ganguly, A., Aral, B., Dionisi-Vici, C., Touati, G., Heinrichs, C., Rabier, D., Kamoun, P., Robert, J.J., Stanley, C., Saudubray, J.M. Pediatr. Res. (2001) [Pubmed]
  16. The human glutamate dehydrogenase gene family: gene organization and structural characterization. Michaelidis, T.M., Tzimagiorgis, G., Moschonas, N.K., Papamatheakis, J. Genomics (1993) [Pubmed]
  17. Three human glutamate dehydrogenase genes (GLUD1, GLUDP2, and GLUDP3) are located on chromosome 10q, but are not closely physically linked. Deloukas, P., Dauwerse, J.G., Moschonas, N.K., van Ommen, G.J., van Loon, A.P. Genomics (1993) [Pubmed]
  18. Properties and molecular evolution of human GLUD2 (neural and testicular tissue-specific) glutamate dehydrogenase. Kanavouras, K., Mastorodemos, V., Borompokas, N., Spanaki, C., Plaitakis, A. J. Neurosci. Res. (2007) [Pubmed]
  19. Structure and expression analysis of a member of the human glutamate dehydrogenase (GLUD) gene family mapped to chromosome 10p11.2. Tzimagiorgis, G., Leversha, M.A., Chroniary, K., Goulielmos, G., Sargent, C.A., Ferguson-Smith, M., Moschonas, N.K. Hum. Genet. (1993) [Pubmed]
  20. Regulation of human glutamate dehydrogenases: implications for glutamate, ammonia and energy metabolism in brain. Plaitakis, A., Zaganas, I. J. Neurosci. Res. (2001) [Pubmed]
  21. Nerve tissue-specific (GLUD2) and housekeeping (GLUD1) human glutamate dehydrogenases are regulated by distinct allosteric mechanisms: implications for biologic function. Plaitakis, A., Metaxari, M., Shashidharan, P. J. Neurochem. (2000) [Pubmed]
  22. Molecular cloning and characterization of placental tissue protein 18 (PP18a)/human mitochondrial branched-chain aminotransferase (BCATm) and its novel alternatively spliced PP18b variant. Than, N.G., Sümegi, B., Than, G.N., Bellyei, S., Bohn, H. Placenta (2001) [Pubmed]
  23. Frontal lobe dysfunction in progressive supranuclear palsy: evidence for oxidative stress and mitochondrial impairment. Albers, D.S., Augood, S.J., Park, L.C., Browne, S.E., Martin, D.M., Adamson, J., Hutton, M., Standaert, D.G., Vonsattel, J.P., Gibson, G.E., Beal, M.F. J. Neurochem. (2000) [Pubmed]
  24. Isolation of RNA polymerase from Clostridium difficile and characterization of glutamate dehydrogenase and rRNA gene promoters in vitro and in vivo. Mani, N., Dupuy, B., Sonenshein, A.L. J. Bacteriol. (2006) [Pubmed]
  25. The effects of an acetate-sensitive anion binding site on NADPH binding in glutamate dehydrogenase. Chalabi, P., Maniscalco, S., Cohn, L.E., Fisher, H.F. Biochim. Biophys. Acta (1987) [Pubmed]
  26. A new enzyme-coupled spectrophotometric method for the determination of arginase activity. Ozer, N. Biochemical medicine. (1985) [Pubmed]
  27. A comparison of the glutamate dehydrogenase catalyzed oxidation of NADPH by trinitrobenzenesulfonate with the uncatalyzed reaction. Brown, A., Fisher, H.F. J. Am. Chem. Soc. (1976) [Pubmed]
  28. Hormonal regulation of glutamine metabolism by OK cells. Nissim, I., States, B., Nissim, I., Lin, Z.P., Yudkoff, M. Kidney Int. (1995) [Pubmed]
  29. ATP production in isolated muscle mitochondria from haemodialysis patients: effects of correction of anaemia with erythropoietin. Bárány, P., Wibom, R., Hultman, E., Bergström, J. Clin. Sci. (1991) [Pubmed]
  30. 15N-NMR study of ammonium assimilation in Agaricus bisporus. Baars, J.J., Op den Camp, H.J., van der Drift, C., Joordens, J.J., Wijmenga, S.S., van Griensven, L.J., Vogels, G.D. Biochim. Biophys. Acta (1996) [Pubmed]
  31. Substitution of Ser for Arg-443 in the regulatory domain of human housekeeping (GLUD1) glutamate dehydrogenase virtually abolishes basal activity and markedly alters the activation of the enzyme by ADP and L-leucine. Zaganas, I., Spanaki, C., Karpusas, M., Plaitakis, A. J. Biol. Chem. (2002) [Pubmed]
  32. Suppression of insulin oversecretion by subcutaneous recombinant human insulin-like growth factor I in children with congenital hyperinsulinism due to defective beta-cell sulfonylurea receptor. Katz, L.E., Ferry, R.J., Stanley, C.A., Collett-Solberg, P.F., Baker, L., Cohen, P. J. Clin. Endocrinol. Metab. (1999) [Pubmed]
  33. Expression, purification and characterization of human glutamate dehydrogenase (GDH) allosteric regulatory mutations. Fang, J., Hsu, B.Y., MacMullen, C.M., Poncz, M., Smith, T.J., Stanley, C.A. Biochem. J. (2002) [Pubmed]
  34. Abnormal glutamate metabolism in an adult-onset degenerative neurological disorder. Plaitakis, A., Berl, S., Yahr, M.D. Science (1982) [Pubmed]
  35. Molecular cloning and nucleotide sequence of the cDNA for human liver glutamate dehydrogenase precursor. Amuro, N., Yamaura, M., Goto, Y., Okazaki, T. Biochem. Biophys. Res. Commun. (1988) [Pubmed]
  36. Heterogeneity of persistent hyperinsulinaemic hypoglycaemia. A series of 175 cases. de Lonlay, P., Fournet, J.C., Touati, G., Groos, M.S., Martin, D., Sevin, C., Delagne, V., Mayaud, C., Chigot, V., Sempoux, C., Brusset, M.C., Laborde, K., Bellane-Chantelot, C., Vassault, A., Rahier, J., Junien, C., Brunelle, F., Nihoul-Fékété, C., Saudubray, J.M., Robert, J.J. Eur. J. Pediatr. (2002) [Pubmed]
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