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

• 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 [5].
• These results seems to indicate that the Tf index is more reliable for the detection of alcohol abuse than liver enzymes such as gammaglutamyl transferase (gamma GT) or glutamate dehydrogenase (GDH) [6].
• The total GDH activity was lower in patients with olivopontocerebellar atrophy (OPCA), motor neuron disease, Parkinson's disease or Alzheimer's disease than in age-matched control subjects, but not in patients with nondegenerative neurological diseases [7].
• High levels of serum GDH activity occurred in those patients with recent excess alcohol consumption independently of the underlying liver histology, and did not discriminate between those patients with and those without alcoholic hepatitis [8].
• The relation between mitochondrial ATP production rate and GDH activity was the same for all subjects irrespective of physical activity status, but MAPRPPKM/kg muscle varied from 6.6 +/- 1.3 mmol.min-1.kg-1 in sedentary subjects to 11.0 +/- 2.2 in highly active subjects [9].

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

• Glutamate dehydrogenase, an enzyme central to glutamate metabolism, is deficient in patients with heterogeneous neurological disorders characterized by multiple system atrophy [3].
• However, they did not fit the characteristics of HI caused by glutamate dehydrogenase gene mutations, previously felt to explain leucine-sensitive hypoglycemia [11].
• Glutamate dehydrogenase (GDH) activity and its allosteric modulation by purine nucleotides were studied in platelet preparations from 4 patients with a nondominant form of adult-onset olivopontocerebellar atrophy (OPCA) and in affected and nonaffected members of two families with a dominant form of OPCA [12].
• Photoaffinity labeling with a specific probe, [(32)P]nicotinamide 2-azidoadenosine dinucleotide, was used to identify the NAD(+) binding site within human GDH encoded by the synthetic human GDH gene and expressed in Escherichia coli as a soluble protein [13].
• Hyperinsulinism/hyperammonemia syndrome in children with regulatory mutations in the inhibitory guanosine triphosphate-binding domain of glutamate dehydrogenase [14].

Biological context of GLUD1

• Heterozygous mutations were localized in the antenna region (four patients in exon 11, two patients in exon 12) as well as in the guanosine triphosphate binding site (two patients in exon 6, two patients in exon 7) of the GLUD1 gene [15].
• Their high degree of similarity to GLUD1 is limited to the region surrounding exons 2, 3, and 4 [16].
• Yeast artificial chromosomes (YACs) of 340 and 370 kb that contain the functional human glutamate dehydrogenase gene (GLUD1) and the pseudogene GLUDP2, respectively, were isolated [17].
• These genes were not physically linked to each other nor to any other sequences homologous to the exons of GLUD1 [17].
• 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 [18].

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

• Nerve tissue-specific (GLUD2) and housekeeping (GLUD1) human glutamate dehydrogenases are regulated by distinct allosteric mechanisms: implications for biologic function [21].
• 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 [21].
• In contrast, GLUD2 GDH activated by ADP and/or L-leucine was amenable to this inhibition, although at substantially higher GTP concentrations than the GLUD1 enzyme [21].
• This finding suggests that constitutively activated GDH enhances oxidation of glutamate, which is intracellularly converted from glutamine to alpha-ketoglutarate, a tricarboxylic acid cycle substrate, which thereby stimulates insulin secretion [4].
• Glutamate dehydrogenase (GDH) is important in normal glucose homeostasis [4].

Physical interactions of GLUD1

• Aminotransferase activity of placental origin PP18 antigens was verified by structural analysis and by a coupled branched-chain aminotransferase/glutamate dehydrogenase assay [22].
• Significant decreases (-39%) in alpha-ketoglutarate dehydrogenase complex/glutamate dehydrogenase ratio and significant increases (+36%) in tissue MDA levels were observed in the SFC in PSP; no differences in complex I or complex IV activities were detected [23].
• That is, C. difficile RNA polymerase was partially purified and shown to bind to and initiate transcription in vitro from bona fide C. difficile promoters for rRNA and glutamate dehydrogenase genes [24].
• The effects of an acetate-sensitive anion binding site on NADPH binding in glutamate dehydrogenase [25].
• Arginase is coupled to urease and glutamate dehydrogenase and the decrease in absorbance at 340 nm due to the oxidation of NADPH is followed [26].

Enzymatic interactions of GLUD1

• A comparison of the glutamate dehydrogenase catalyzed oxidation of NADPH by trinitrobenzenesulfonate with the uncatalyzed reaction [27].

Regulatory relationships of GLUD1

• PTH and acute acidosis significantly stimulated glutamine metabolism via both the phosphate-dependent glutaminase (PDG) and glutamate dehydrogenase (GLDH) pathways [28].
• The ratio between ATP production rate and glutamate dehydrogenase activity was on average 40% higher in the patients at the start and decreased towards the control level in six out of seven patients after 1 year on maintenance erythropoietin treatment [29].
• Participation of glutamine synthetase, glutamate synthase and NADP-dependent glutamate dehydrogenase was determined by inhibiting glutamine synthetase with phosphinothricin and glutamate synthase with azaserine [30].

Other interactions of GLUD1

• To determine the structural basis of these functional differences, we mutagenized the GLUD1 GDH at four residues that differ from those of the GLUD2 isoenzyme [31].
• We enrolled nine subjects in an open label trial of rhIGF-I: eight children, ages 1 month to 11 yr, with HI due to identified mutations of SUR1 (n = 5) or clinically unresponsive to diazoxide, which acts via the SUR (n = 3), and one adult, age 32 yr, with HI due to defective glutamate dehydrogenase-1 [32].
• Fluorescence in situ hybridization using the entire cosmid as a probe, mapped this GLUD gene locus, termed GLUDP5, to chromosome 10p11.2 [19].
• Two distinct GLUD-specific gene loci, termed GLUDP2 and GLUDP3, possibly represent truncated pseudogenes [16].
• 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 [18].

Analytical, diagnostic and therapeutic context of GLUD1

• 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 [5].
• These data confirm the assignment of the GTP and ADP allosteric regulatory sites on GDH based on X-ray crystallography and provide insight into the structural mechanisms involved in positive and negative allosteric control and in inter-subunit co-operativity of human GDH [33].
• Oral administration of monosodium glutamate resulted in excessive accumulation of this amino acid in plasma and lack of increase in the ratio of plasma lactate to pyruvate in the glutamate dehydrogenase-deficient patients [34].
• Molecular cloning and nucleotide sequence of the cDNA for human liver glutamate dehydrogenase precursor [35].
• Ten patients with hyperinsulinism-hyperammonaemia syndrome had a mutation in the glutamate dehydrogenase gene (three neonates and seven infants) after reverse transcriptase-polymerase chain reaction and sequence analysis of cDNA [36].

References