Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.4.1.2 (glutamate dehydrogenase)
4,380 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Parkinson's disease (PD) is associated with degeneration of the pigmented dopaminergic neurons located in the ventral mesencephalon. Although the mechanisms by which these neurons degenerate in PD are poorly understood, indirect evidence suggests involvement of glutamatergic mechanisms in the pathogenesis of this disorder. Glutamate, the major excitatory transmitter in the mammalian central nervous system, is known to be neurotoxic when present in excess at the synapses. Two major mechanisms protect neurons from glutamate-induced toxicity: (a) removal of synaptic glutamate via a high affinity uptake carried out by cytoplasmic membrane proteins known as excitatory amino acid transporters (EAAT); and (b) metabolism and recycling of glutamate by synaptic astrocytes via glutamine synthetase, an ATP-requiring reaction. However, when extra-cellular glutamate levels are high (0.5-1.0 mM), glutamate metabolism may be shifted toward the ATP-generating oxidative deamination (glutamate dehydrogenase)-TCA cycle pathway. We have cloned and characterized two human glutamate dehydrogenases (GDH), one of which is nerve tissue specific. This isoenzyme requires ADP for its activity and it may become functional when cellular energy charge is low. We have also cloned three human glutamate transporters. One of these (EAAT3) is neuron specific. In situ hybridization studies using human brain revealed that the pigmented dopaminergic neurons, which degenerate in PD, express EAAT3 at high levels. Primary nerve tissue cultures derived from rat ventral mesencephalon were established and studied for their ability to metabolize glutamate. Results showed that mature cultures expressing high levels of GDH activity were capable of rapidly utilizing glutamate added to the medium at high concentrations (1-1.2 mM). This was associated with little release of aspartate and alanine into the medium. In contrast, immature cultures expressing low GDH activity utilized glutamate at lower rates while releasing substantial amounts of aspartate and alanine into the medium. These data suggest that immature mesencephalic cells metabolize a substantial fraction of the glutamate they take up from the medium via the transamination pathway, compared to mature mesencephalic cultures. Immunocytochemical studies on these cultures revealed that dopaminergic neurons (identified by their tyrosine hydroxylase content) showed intense staining for GDH. Furthermore, inhibition of GDH expression by antisense oligonucleotides was toxic to cultured mesencephalic neurons, with dopaminergic neurons being affected at the early stages of this inhibition. Hence, the dense expression by dopaminergic neurons of proteins involved in the transport and metabolism of glutamate may serve particular biological needs intrinsic to these cells. Further studies are required to test whether these properties render these neurons vulnerable to excitotoxic mechanisms or to abnormalities of glutamate metabolism.
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PMID:Glutamate transport and metabolism in dopaminergic neurons of substantia nigra: implications for the pathogenesis of Parkinson's disease. 1099 62

The relative contribution of glutamate dehydrogenase (GDH) and the aminotransferase activity to mitochondrial glutamate metabolism was investigated in dilute suspensions of purified mitochondria from potato (Solanum tuberosum) tubers. Measurements of glutamate-dependent oxygen consumption by mitochondria in different metabolic states were complemented by novel in situ NMR assays of specific enzymes that metabolize glutamate. First, a new assay for aminotransferase activity, based on the exchange of deuterium between deuterated water and glutamate, provided a method for establishing the effectiveness of the aminotransferase inhibitor amino-oxyacetate in situ, and thus allowed the contribution of the aminotransferase activity to glutamate oxidation to be assessed unambiguously. Secondly, the activity of GDH in the mitochondria was monitored in a coupled assay in which glutamine synthetase was used to trap the ammonium released by the oxidative deamination of glutamate. Thirdly, the reversibility of the GDH reaction was investigated by monitoring the isotopic exchange between glutamate and [(15)N]ammonium. These novel approaches show that the oxidative deamination of glutamate can make a significant contribution to mitochondrial glutamate metabolism and that GDH can support the aminotransferases in funneling carbon from glutamate into the TCA cycle.
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PMID:Contribution of glutamate dehydrogenase to mitochondrial glutamate metabolism studied by (13)C and (31)P nuclear magnetic resonance. 1118 11

The activity level and some physico-chemical properties of enzymes of the tricarboxylic acid cycle (TCA cycle) and the associated enzymes isocitrate lyase and glutamate dehydrogenase of cyanobacterium Spirulina platensis grown under illumination of 5000 lk in batch conditions, have been studied. High activities of most of the studied enzymes except for alpha-ketoglutarate dehydrogenase (alpha-KGDH) and succinate dehydrogenase have been estimated. In some cases the activities were by an order higher than that of similar enzymes in other cyanobacteria. This reflects the microorganism ability to synthesize intensively organic substances and first of all protein. Absence of alpha-KGDH activity proves that TCA cycle of spirulina has a limited value for energy generation and mainly performs the biosynthetic function.
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PMID:[Activity of tricarboxylic acid cycle enzymes in cyanobacteria Spirulina platensis]. 1130 83

Leucine and glutamine were used to elicit biphasic insulin release in rat pancreatic islets. Leucine did not mimic the full biphasic response of glucose. Glutamine was without effect. However, the combination of the two did mimic the biphasic response. When the ATP-sensitive K+ (KATP) channel-independent pathway was studied in the presence of diazoxide and KCl, leucine and its nonmetabolizable analog 2-aminobicyclo[2,2,1]heptane-2-carboxylic acid (BCH) both stimulated insulin secretion to a greater extent than glucose. Glutamine and dimethyl glutamate had no effect. Because the only known action of BCH is stimulation of glutamate dehydrogenase, this is sufficient to develop the full effect of the KATP channel-independent pathway. Glucose, leucine, and BCH had no effect on intracellular citrate levels. Leucine and BCH both decreased glutamate levels, whereas glucose was without effect. Glucose and leucine decreased palmitate oxidation and increased esterification. Strikingly, BCH had no effect on palmitate oxidation or esterification. Thus BCH activates the KATP channel-independent pathway of glucose signaling without raising citrate levels, without decreasing fatty acid oxidation, and without mimicking the effects of glucose and leucine on esterification. The results indicate that increased flux through the TCA cycle is sufficient to activate the KATP channel-independent pathway.
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PMID:Activation of the KATP channel-independent signaling pathway by the nonhydrolyzable analog of leucine, BCH. 1270 98

Measurements of the specific activities of the representative enzymes of different pathways linked to carbohydrate metabolism indicate that glycolysis and TCA cycles are the major route of carbohydrate catabolism in the sporulating phase of fruiting body development in Pleurotus ostreatus. Enzymes of the pentose phosphate pathway always showed lower specific activities as compared to those of the enzymes of the glycolytic pathway. The activity of NADP linked glutamate dehydrogenase which is known to be an anabolic enzyme decreased drastically in sporulating fruiting bodies and in spore containing gill tissue (spore bearing structure). Mannitol dehydrogenase activity declined significantly in the sporulating phase of P. ostreatus. The high rate of metabolism during sporulation was further supported by a lower rate of gluconeogenesis at this stage. Concentrations of all the major sugars of the fruiting body (mannitol, glucose and trehalose) decreased in the mature fruiting body and gill tissue. This indicated high catabolic activities at this stage of development.
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PMID:Evidences of high carbon catabolic enzyme activities during sporulation of Pleurotus ostreatus (Florida). 1462 96

In this article, we advocate the radical revision of the 20th-century version of amino acid metabolism as follows. (1) Classic studies on the incorporation of [15N]ammonia into glutamate, once considered to be an epoch-making event, are not distinctive proof of the ability of animals to utilize ammonia for the synthesis of alpha-amino nitrogen. (2) Mammalian glutamate dehydrogenase has been implicated to function as a glutamate-synthesizing enzyme albeit lack of convincing proof. This enzyme, in combination with aminotransferases, is now known to play an exclusive role in the metabolic removal of amino nitrogen and energy production from excess amino acids. (3) Dr. William C Rose's "nutritionally nonessential amino acids" are, of course, essential in cellular metabolism; the nutritional nonessentiality is related to their carbon skeletons, many of which are intermediates of glycolysis or the TCA cycle. Obviously, the prime importance of amino acid nutrition should be the means of obtaining amino nitrogen. (4) Because there is no evidence of the presence of any glutamate-synthesizing enzymes in mammalian tissues, animals must depend on plants and microorganisms for preformed alpha-amino nitrogen. This is analogous to the case of carbohydrates. (5) In contrast, individual essential amino acids, similar to vitamins and essential fatty acids, should be considered important nutrients that must be included regularly in sufficient amounts in the diet.
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PMID:Reappraisal of the 20th-century version of amino acid metabolism. 1463 43

Fluoroacetate (FA; CH2FCOOR) is highly toxic towards humans and other mammals through inhibition of the enzyme aconitase in the tricarboxylic acid cycle, caused by 'lethal synthesis' of an isomer of fluorocitrate (FC). FA is found in a range of plant species and their ingestion can cause the death of ruminant animals. Some fluorinated compounds -- used as anticancer agents, narcotic analgesics, pesticides or industrial chemicals -- metabolize to FA as intermediate products. The chemical characteristics of FA and the clinical signs of intoxication warrant the re-evaluation of the toxic danger of FA and renewed efforts in the search for effective therapeutic means. Antidotal therapy for FA intoxication has been aimed at preventing fluorocitrate synthesis and aconitase blockade in mitochondria, and at providing citrate outflow from this organelle. Despite a greatly improved understanding of the biochemical mechanism of FA toxicity, ethanol, if taken immediately after the poisoning, has been the most acceptable antidote for the past six decades. This review deals with the clinical signs and physiological and biochemical mechanisms of FA intoxication to provide an explanation of why, even after decades of investigation, has no effective therapy to FA intoxication been elaborated. An apparent lack of integrated toxicological studies is viewed as a limiter of progress in this regard. Two principal ways of developing effective therapies for FA intoxication are considered. Firstly, competitive inhibition of FA interaction with CoA and of FC interaction with aconitase. Secondly, channeling the alternative metabolic pathways by orienting the fate of citrate via cytosolic aconitase, and by maintaining the flux of reducing equivalents into the TCA cycle via glutamate dehydrogenase.
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PMID:Toxicology of fluoroacetate: a review, with possible directions for therapy research. 1625 58

Understanding the functional genomics and proteomics of plasmodia underpins the development of new approaches to antimalarial chemotherapy. Although genome databanks (e.g. PlasmoDB) and biocomputing tools (e.g. PlasMit, PlasmoAP, PATS) are useful in providing a global albeit predictive view of the myriad of about 5000 genes, only 40% are annotated, with few cases of endorsed subcellular localizations of the corresponding proteins in animal models. Progress in plasmodial protein trafficking has been hampered by the lack of a simple yet reliable method for studying subcellular localization of plasmodial proteins. In this study, we have used a combination of fluorescent markers, organelle-specific probes, phase contrast microscopy, and confocal microscopy to locate a selection of signal peptides from 10 plasmodial proteins in CHO-K1 cells. These eukaryotic cells serve as an in vitro living system for studying the cellular destinations of four mitochondrial-targeted TCA cycle proteins (citrate synthase, CS; isocitrate dehydrogenase, ICDH; branched chain alpha-keto-acid dehydrogenase E1alpha subunit, BCKDH; succinate dehydrogenase flavoprotein-subunit, SDH), two nuclear-targeted proteins (histone deacetylase, HDAC; RNA polymerase, RPOL), two apicoplast-targeted proteins (pyruvate kinase 2, PK2; glutamate dehydrogenase, GDH), and two cytoplasmic resident proteins (malate dehydrogenase, MDH; glycerol kinase, GK). The respective localizations of these malarial proteins have complied with the selected molecular targets, viz. mitochondrial, nuclear and cytoplasmic. Interestingly, MDH that is widely known to be resident in eukaryotic mitochondria was found to be cytoplasmic, probably due to the absence of molecular target sequences. Since the localization of plasmodial proteins is central to the authentication of their pathophysiological roles, this experimental system will serve as a useful a priori approach.
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PMID:A relevant in vitro eukaryotic live-cell system for the evaluation of plasmodial protein localization. 1683 57

Interconversion between glutamate and 2-oxoglutarate, which can be catalysed by glutamate dehydrogenase (GDH), is a key reaction in plant carbon (C) and nitrogen (N) metabolism. However, the physiological role of plant GDH has been a controversial issue for several decades. To elucidate the function of GDH, the expression of GDH in various tissues of Arabidopsis thaliana was studied. Results suggested that the expression of two Arabidopsis GDH genes was differently regulated depending on the organ/tissue types and cellular C availability. Moreover, Arabidopsis mutants defective in GDH genes were identified and characterized. The two isolated mutants, gdh1-2 and gdh2-1, were crossed to make a double knockout mutant, gdh1-2/gdh2-1, which contained negligible levels of NAD(H)-dependent GDH activity. Phenotypic analysis on these mutants revealed an increased susceptibility of gdh1-2/gdh2-1 plants to C-deficient conditions. This conditional phenotype of the double knockout mutant supports the catabolic role of GDH and its role in fuelling the TCA cycle during C starvation. The reduced rate of glutamate catabolism in the gdh2-1 and gdh1-2/gdh2-1 plants was also evident by the growth retardation of these mutants when glutamate was supplied as the alternative N source. Furthermore, amino acid profiles during prolonged dark conditions were significantly different between WT and the gdh mutant plants. For instance, glutamate levels increased in WT plants but decreased in gdh1-2/gdh2-1 plants, and aberrant accumulation of several amino acids was detected in the gdh1-2/gdh2-1 plants. These results suggest that GDH plays a central role in amino acid breakdown under C-deficient conditions.
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PMID:NAD(H)-dependent glutamate dehydrogenase is essential for the survival of Arabidopsis thaliana during dark-induced carbon starvation. 1829 29

Extension of a single cell model of E. coli B/r to make predictions of culture response to variations in glutamine/glucose/ammonium ion concentrations is described. A biphasic glutamine transport system, a nitrogen metabolism scheme that includes glutamate dehydrogenase (GDH), glutamine synthetase/glutamate synthase (GS/GOGAT), the glutaminase routes, and a transaminase mechanism for glutamine carbon usage are added to the prototype model. The predictions of the extended model with regard to nutrient concentrations and cell size compare well with the experimental data and the prototype model predictions, demonstrating the capability of the integrated kinetic model to illustrate important enzymological interactions in a biological system. The discrepancies between the experimental data and the model predictions on growth yield suggest that a more detailed regulatory system of the TCA cycle is required for a more accurate energy budget.
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PMID:A mathematical model for the growth of a single cell of E. coli on a glucose/glutamine/ammonium medium. 1858 29


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