Disease relevance of GLUD2

• Loss of SIRT4 in insulinoma cells activates GDH, thereby upregulating amino acid-stimulated insulin secretion [1].
• Serum glutamate dehydrogenase (GDH) activity was greatly raised (up to 830 times the upper limit of normal) in 16 patients with Reye's syndrome [2].
• The H454Y GDH transgenic mice had hypoglycemia with normal growth rates [3].
• However, on the basis of the three-dimensional structure of the NAD(+)-linked glutamate dehydrogenase (GDH) from Clostridium symbiosum we have demonstrated that this residue is not a universal requirement for the construction of an NAD+ binding site [4].
• Results were compared to children with genetic hyperinsulinism due to mutations of the adenosine triphosphate-dependent potassium (K(ATP)) channel and glutamate dehydrogenase (GDH) [5].

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

• From 21 patients with spinocerebellar degeneration 5 had markedly decreased glutamate dehydrogenase (GDH) activities and high values of serum plasma glutamate level after oral glutamate loading tests [7].

Biological context of GLUD2

• Properties and molecular evolution of human GLUD2 (neural and testicular tissue-specific) glutamate dehydrogenase [8].
• There is evolutionary evidence that the GLUD1 was retroposed to the X chromosome in the ape ancestor (<23 million years ago), where it gave rise to GLUD2 through random mutations and directional selection [8].
• More precise localisations of the glutamate dehydrogenase gene (GLUD) to chromosome 10q23 and of the pseudogene GLUDP1 to X q24 are proposed [9].
• H454Y transgene expression was confirmed by increased GDH enzyme activity in islets and decreased sensitivity to GTP inhibition [3].
• Stimulation of insulin release by the H454Y GDH mutation or by leucine activation is associated with increased oxidative deamination of glutamate via GDH [3].

Anatomical context of GLUD2

• Hence, substitution of Ser for Arg443 and Ala for Gly456 are the main evolutionary changes that led to the adaptation of the GLUD2 GDH to the unique metabolic needs of the nerve tissue [10].
• In all three patient groups, GDH activity was considerably lower, and AAT and LDH activities were higher in cortex of MTLE as compared with the corresponding activities in hippocampus (p<0.05) [11].
• Differential glutamate dehydrogenase (GDH) activity profile in patients with temporal lobe epilepsy [11].
• The activity of total and heat-stable glutamate dehydrogenase (GDH) in lymphocytes increased with aging in 40 control subjects (p less than 0.001) [12].
• The effect of nucleotides: AMP, cAMP, ADP, ATP, GDP and GTP, on glutamate dehydrogenase (GDH) purified from the mealworm fat body was studied [13].

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

• The GLUD2 gene was screened for mutations by Southern hybridization and by direct sequencing of polymerase chain reaction (PCR) products [15].
• We compared a recently marketed enzyme immunoassay for glutamate dehydrogenase (GDH), TechLab's C [19].
• Immunochemical analyses (Western blots) of cerebellar homogenates for glutamate dehydrogenase (GDH) from patients with spinocerebellar degeneration and control subjects were conducted [20].
• In this paper we have tested two different procedures (the "three-step" and the "four-step" procedures) for the covalent immobilization of glutamate dehydrogenase (GDH) onto silicon supports [21].
• The 2D imaging biosensor, designed for sensitive glutamate monitoring, is prepared through the use of a flat silica plate that is covalently attached with an enzyme, glutamate dehydrogenase (GDH) [22].

References