Disease relevance of Glud1

• The data explain "leucine-hypersensitivity" of beta-cells during hypoglycemia and contribute to the elucidation of the GDH-linked syndrome of hyperinsulinism associated with elevated serum ammonia levels [1].
• Identification of regulatory mutations of glutamate dehydrogenase (GDH) in a form of congenital hyperinsulinism (GDH-HI) is providing a model for basal insulin secretion (IS) and amino acid (AA)-stimulated insulin secretion (AASIS) in which glutaminolysis plays a key role [2].
• GDH-HI mutations impair GDH sensitivity to GTP inhibition, leading to fasting hypoglycemia, leucine hypersensitivity, and protein-induced hypoglycemia, indicating the importance of GDH in basal secretion and AASIS [2].
• Polyclonal antisera raised against the GLDH of Proteus spp. cross-reacted with GLDH from P. falciparum [3].
• Glutamate dehydrogenase activity in subcellular fractions of mouse fibrosarcoma [4].

High impact information on Glud1

• Re-exposure of the cells from the low O2 environment to high O2 conditions for an additional 4 days caused a rise in the GDH activity and a decrease in the LDH and PK [5].
• Thus glutamate dehydrogenase per se, and not glutamate penetration, constitutes the control step for gluttochondria of glutamate with externally added oxaloacetate (arsenite present) that exclude an obligatory transport of oxaloacetate on the alpha-oxoglutarate carrier [6].
• Treatment of H8 recipient mice with agonistic anti-CD40 Abs induced vigorous expansion of the transferred P14 T cells and led to liver cell destruction determined by increase of glutamate dehydrogenase serum levels and induction of caspase-3 in hepatocytes [7].
• The proposed model for glutaminolysis in IS is based on GDH providing NADH and alpha-ketoglutarate (alpha-KG) to the Krebs cycle, hence increasing the beta-cell ATP-to-ADP ratio to effect insulin release [2].
• Demonstration of glutamate dehydrogenase isozymes in beef heart mitochondria [8].

Chemical compound and disease context of Glud1

• Mice injected with sodium nitroprusside (NaNP) exhibited a marked, transient hyperglycemia and enhanced activity of glutamate dehydrogenase in the pancreatic islets [9].
• Flow cytometric measurements of the activities of lactate dehydrogenase, glucose-6-phosphate dehydrogenase, isocitrate dehydrogenase, glycerol-3-phosphate dehydrogenase, succinate dehydrogenase and glutamate dehydrogenase in single Ehrlich ascites tumour cells are described using a tetrazolium salt/fluorescent formazan reaction [10].

Biological context of Glud1

• Chromosomal mapping of glutamate dehydrogenase gene sequences to mouse chromosomes 7 and 14 [11].
• The 3.5-kb transcript is prominent in rat brain, whereas the 2.8-kb transcript is barely detectable, a result suggesting that GDH gene expression is differentially controlled in rat brain [12].
• Fourteen differences between the amino acid sequence deduced from this cDNA and the sequence reported for human liver GDH suggest that there may be two active human GDH genes [12].
• (5) The effects of other branched-chain amino acids on oxidative phosphorylation resembled their effects on insulin release, redox state of nicotinamide nucleotides and glutamate dehydrogenase activity [13].
• In GAD67-expressing astrocytes, the glutamate was mainly converted into GABA, suggesting GAD transgene activity to be dominant over other glutamate metabolic pathways, such as glutamine synthetase and glutamate dehydrogenase [14].

Anatomical context of Glud1

• In connection with the ability of L-leucine to activate glutamate dehydrogenase, this high activity of the branched-chain amino acid aminotransferase in pancreatic B-cell mitochondria may provide an explanation for the insulin secretory potency of this amino acid [15].
• These data correlate well with the intense immunoreactivity to GDH in Golgi-Bergmann astrocytes in vivo that has been recently reported [16].
• Glutamate dehydrogenase activity is markedly higher in a "Golgi-Bergmann"-like glial clone than in other astroglial cell lines [16].
• Glutamate dehydrogenase is the sensor of leucine, whereas transamination plays an important role in KIC stimulation of pancreatic beta-cells [17].
• Here we report that glutamate dehydrogenase (GDH) stimulates polyclonal proliferation and differentiation of naive B cells [18].

Associations of Glud1 with chemical compounds

• Leucine and ADP are activators and GTP is an inhibitor of GDH [2].
• Enzyme analyses of culture medium and cell homogenates have detected some enzymes characteristic of liver tissue such as gamma-glutamyl transferase, sorbital dehydrogenase, alkaline phosphatase, glutamate dehydrogenase, as well as aspartate and alanine transaminase [19].
• For example, the enzyme 6-phosphogluconate dehydrogenase has a much higher average heterozygosity than glutamate dehydrogenase [20].
• The activities of another cytosolic enzyme, lactate dehydrogenase, the mitochondrial enzymes glutamate dehydrogenase, succinate dehydrogenase, cytochrome c oxidase and the activity of the lysosomal enzymes acid phosphatase and beta-glucuronidase were, initially, not or only slightly affected [21].
• When combined preparations of mitochondria and lysosomes are irradiated, inactivation of enzymes occurs in the following order: succinate dehydrogenase greater than glutamate dehydrogenase greater than acid phosphatase greater than beta-glucuronidase [22].
• Isolated islets with either constitutive or acute adenovirus-mediated knock-out of GDH showed a 49 and 38% reduction in glucose-induced insulin release, respectively [23].

Other interactions of Glud1

• The decreased activity of FAD-linked glycerophosphate dehydrogenase contrasted with a normal activity of glutamate dehydrogenase and 2-ketoglutarate dehydrogenase in the islets of db/db mice [24].
• Acetylcholinesterase, glutamine synthetase, acid phosphatase and glutamate dehydrogenase activity in brain and cholinesterase activity in blood were investigated in mice exposed to 170 p.p.m. trichloroethylene (TCE) during 30 days [25].
• In agreement with this observation, activities of the ammoniagenic enzymes, glutaminase and glutamate dehydrogenase, were not different in the renal cortex of fed and starved mice, but the glutamate dehydrogenase mRNA level was elevated 4.5-fold in the renal cortex from starved mice [26].
• (2) The specific activities of carbamoyl-phosphate synthetase (ammonia) and glutamate dehydrogenase are about 15% lower than normal in mitochondria from spfash mice, whereas those of beta-hydroxybutyrate dehydrogenase and cytochrome oxidase are 22% higher and 30% lower respectively [27].
• An N-terminal sequence of the 50 kDa adduct was 100% homologous with the deduced amino acid sequence of glutamate dehydrogenase [28].

Analytical, diagnostic and therapeutic context of Glud1

• We conclude, for the moment, that none of these cerebellar mutant mice can be considered as an animal model for GDH-deficient MSA [29].
• Molecular cloning, structure and expression analysis of a full-length mouse brain glutamate dehydrogenase cDNA [30].
• The GLDH of P. falciparum was shown to be a cytosolic protein (by FAT) with a subunit molecular weight of approximately 49 000 Da (by immunoprecipitation) having a predominantly hexameric form (by sucrose density gradient) [3].

References