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GLUD2  -  glutamate dehydrogenase 2

Homo sapiens

Synonyms: GDH 2, GDH2, GLUDP1, Glutamate dehydrogenase 2, mitochondrial
 
 
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Disease relevance of GLUD2

 

High impact information on GLUD2

  • GDH is known to promote the metabolism of glutamate and glutamine, generating ATP, which promotes insulin secretion [1].
  • 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 [1].
  • Furthermore, GDH from SIRT4-deficient or CR mice is insensitive to phosphodiesterase, an enzyme that cleaves ADP-ribose, suggesting the absence of ADP-ribosylation [1].
  • There was marked reduction in the activity of glutamate dehydrogenase (GDH) (22% of mean control activity); GDH activity was also decreased in homogenates of leukocytes from this patient (38% of mean control activity) [6].
  • High glucose inhibited both glutaminase and GDH flux, and leucine could not override this inhibition [3].
 

Chemical compound and disease context of GLUD2

 

Biological context of GLUD2

 

Anatomical context of GLUD2

 

Associations of GLUD2 with chemical compounds

  • The GLUD2-derived GDH shows low basal activity and has the capacity to be activated fully by ADP or L-leucine [14].
  • The intronless gene GLUD2, located in Xq25 and expressed in neuronal and testicular tissues, is involved in the metabolism of glutamate, a neurotransmitter reported to be elevated in the spinal fluid of RTT individuals [15].
  • Kinetic studies revealed significant differences in the K:(m) values obtained for alpha-ketoglutarate and glutamate for the GLUD1- and the GLUD2-derived GDH, with the allosteric activators differentially altering these values [16].
  • Here, a 55 kDa protein, glutamate dehydrogenase (GDH), was established as a specific acceptor for enzymatic, cysteine-specific ADP-ribosylation in mitochondria [17].
  • The H454Y transgene in islets had higher insulin secretion in response to glutamine alone and had 2-fold greater GDH flux [3].
 

Other interactions of GLUD2

  • To identify the structural basis for these allosteric characteristics, we performed site-directed mutagenesis on the human GLUD1 gene at sites that differ from the GLUD2 gene using a cloned GLUD1 cDNA [18].
  • Therefore, GLUD2 and GDI1 can be excluded as candidate genes for this syndrome [15].
  • Study of structure-function relationships, using site-directed mutagenesis of GLUD1 at single sites differing from GLUD2, showed that the Arg443Ser and the Gly456Ala change reproduced some, but not all, of the properties of hGDH2 [8].
 

Analytical, diagnostic and therapeutic context of GLUD2

References

  1. 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]
  2. Masking by enzyme inhibitor of raised serum glutamate dehydrogenase activity in Reye's syndrome. Holt, J.T., Arvan, D.A., Mayer, T.K. Lancet (1983) [Pubmed]
  3. Effects of a GTP-insensitive mutation of glutamate dehydrogenase on insulin secretion in transgenic mice. Li, C., Matter, A., Kelly, A., Petty, T.J., Najafi, H., MacMullen, C., Daikhin, Y., Nissim, I., Lazarow, A., Kwagh, J., Collins, H.W., Hsu, B.Y., Nissim, I., Yudkoff, M., Matschinsky, F.M., Stanley, C.A. J. Biol. Chem. (2006) [Pubmed]
  4. Structural consequences of sequence patterns in the fingerprint region of the nucleotide binding fold. Implications for nucleotide specificity. Baker, P.J., Britton, K.L., Rice, D.W., Rob, A., Stillman, T.J. J. Mol. Biol. (1992) [Pubmed]
  5. Clinical features and insulin regulation in infants with a syndrome of prolonged neonatal hyperinsulinism. Hoe, F.M., Thornton, P.S., Wanner, L.A., Steinkrauss, L., Simmons, R.A., Stanley, C.A. J. Pediatr. (2006) [Pubmed]
  6. Glutamate dehydrogenase deficiency in three patients with spinocerebellar syndrome. Plaitakis, A., Nicklas, W.J., Desnick, R.J. Ann. Neurol. (1980) [Pubmed]
  7. Glutamate metabolism of leukocytes and skin fibroblasts in spinocerebellar degeneration with lowered glutamate dehydrogenase activity. Tatsumi, C., Yorifuji, S., Kajiyama, K., Ueno, S., Takahashi, M., Tarui, S. Acta neurologica Scandinavica. (1989) [Pubmed]
  8. 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]
  9. Assignment of the GDH loci to human chromosomes 10q23 and Xq24 by in situ hybridization. Jung, K.Y., Warter, S., Rumpler, Y. Ann. Genet. (1989) [Pubmed]
  10. Study of structure-function relationships in human glutamate dehydrogenases reveals novel molecular mechanisms for the regulation of the nerve tissue-specific (GLUD2) isoenzyme. Plaitakis, A., Spanaki, C., Mastorodemos, V., Zaganas, I. Neurochem. Int. (2003) [Pubmed]
  11. Differential glutamate dehydrogenase (GDH) activity profile in patients with temporal lobe epilepsy. Malthankar-Phatak, G.H., de Lanerolle, N., Eid, T., Spencer, D.D., Behar, K.L., Spencer, S.S., Kim, J.H., Lai, J.C. Epilepsia (2006) [Pubmed]
  12. Lymphocyte glutamate dehydrogenase activity in normal aging and neurological diseases. Iwatsuji, K., Nakamura, S., Kameyama, M. Gerontology. (1989) [Pubmed]
  13. The effect of nucleotides on glutamate dehydrogenase from the mealworm fat body. Teller, J.K. Arch. Int. Physiol. Biochim. (1987) [Pubmed]
  14. Molecular basis of human glutamate dehydrogenase regulation under changing energy demands. Mastorodemos, V., Zaganas, I., Spanaki, C., Bessa, M., Plaitakis, A. J. Neurosci. Res. (2005) [Pubmed]
  15. Evaluation of two X chromosomal candidate genes for Rett syndrome: glutamate dehydrogenase-2 (GLUD2) and rab GDP-dissociation inhibitor (GDI1). Wan, M., Francke, U. Am. J. Med. Genet. (1998) [Pubmed]
  16. 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]
  17. Regulation of glutamate dehydrogenase by reversible ADP-ribosylation in mitochondria. Herrero-Yraola, A., Bakhit, S.M., Franke, P., Weise, C., Schweiger, M., Jorcke, D., Ziegler, M. EMBO J. (2001) [Pubmed]
  18. 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]
  19. Performance of the TechLab C. DIFF CHEK-60 enzyme immunoassay (EIA) in combination with the C. difficile Tox A/B II EIA kit, the Triage C. difficile panel immunoassay, and a cytotoxin assay for diagnosis of Clostridium difficile-associated diarrhea. Snell, H., Ramos, M., Longo, S., John, M., Hussain, Z. J. Clin. Microbiol. (2004) [Pubmed]
  20. Normal cerebellar glutamate dehydrogenase protein in spinocerebellar degeneration. Rosenberg, R.N., Banner, C. J. Neurol. Neurosurg. Psychiatr. (1989) [Pubmed]
  21. Formation and characterization of glutamate dehydrogenase monolayers on silicon supports. Blasi, L., Longo, L., Pompa, P.P., Manna, L., Ciccarella, G., Vasapollo, G., Cingolani, R., Rinaldi, R., Rizzello, A., Acierno, R., Storelli, C., Maffia, M. Biosensors & bioelectronics. (2005) [Pubmed]
  22. A two-dimensional imaging biosensor to monitor enhanced brain glutamate release stimulated by nicotine. Qhobosheane, M., Wu, D., Gu, Y., Tan, W. J. Neurosci. Methods (2004) [Pubmed]
 
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