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:1.4.3.11 (glutamate dehydrogenase)
4,437 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glutamate is believed to be an excitatory amino acid neurotransmitter in the retina. Enzymes for glutamate metabolism, such as glutamate dehydrogenase, ornithine aminotransferase, glutaminase, and aspartate aminotransferase (AAT), exist mainly in the mitochondria. The abnormal increase of intracellular calcium ions in ischemic retinal cells may cause an influx of calcium ions into the mitochondria, subsequently affecting various mitochondrial enzyme activities through the activity of mitochondrial calpain. As AAT has the highest level of activity among enzymes involved in glutamate metabolism, we investigated the change of AAT activity in ischemic and hypoxic rat retinas and the protection against such activity by calpain inhibitors. We used normal RCS (rdy+/rdy+) rats. For the in vivo studies, we clamped the optic nerve of anesthetized rats to induce ischemia. In the in vitro studies, the eye cups were incubated with Locke's solution saturated with 95% N2/5% CO2. The activity of cytosolic AAT (cAAT) was about 20% of total activity, whereas mitochondrial AAT (mAAT) was about 75% in rat retina. Ninety minutes of ischemia or hypoxia caused a 20% decrease in mAAT activity, whereas cAAT activity remained unchanged. To examine the contribution of intracellular calcium ions to the degradation of mAAT, we used Ca2+-free Locke's solution containing 1 mM EGTA, ryanodine (Ca2+ channel blocker), and thapsigargin (Ca2+-ATPase inhibitor). In the present study, thapsigargin in Ca2+-free Locke's solution, but not ryanodine in this solution, was found to prevent AAT degradation. AAT degradation was also prevented by calpain inhibitors (Ca2+-dependent protease inhibitor) such as calpeptin at 1 nM, 10 nM, 0.1 microM, 1 microM and 10 microM, and by calpain inhibitor peptide, but not by other protease inhibitors (10 microM leupeptin, pepstatin, chymostatin). Additionally, we determined the subcellular localization of calpain activity and examined the change of calpain activity in ischemic rat retinas. Our results suggest that decreased activity of mAAT in ischemic and hypoxic rat retinas might be evoked by the degradation by calpain-catalyzed proteolysis in mitochondria.
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PMID:Possible mechanism for the decrease of mitochondrial aspartate aminotransferase activity in ischemic and hypoxic rat retinas. 1039 49

During normal acid-base balance, the kidney extracts very little of the plasma glutamine. However, during metabolic acidosis, as much as one third of the plasma glutamine is extracted and metabolized in a single pass through this organ. The substantial increase in renal utilization occurs solely within the proximal convoluted tubule and is sustained by compensating adaptations in the intraorgan metabolism of glutamine. The primary pathway for renal glutamine metabolism involves its transport into mitochondria and its deamidation and deamination by glutaminase (GA) and glutamate dehydrogenase (GDH), respectively. The resulting ammonium ions are excreted predominantly in the urine where they function as expendable cations to facilitate the excretion of acids. The resulting alpha-ketoglutarate is further metabolized to phosphoenolpyruvate and subsequently to glucose or CO2. The intermediate steps yield two bicarbonate ions that are selectively transported into the venous blood to partially compensate the metabolic acidosis. In rat kidney, this adaptation is sustained in part by the cell-specific induction of the glutaminase that results primarily from stabilization of the GA mRNA. The 3'-nontranslated region of the GA mRNA contains a direct repeat of an 8-base AU-sequence that functions as a pH-response element. This sequence exhibits a high affinity and specificity for zeta (z)-crystallin. The same protein binds to two separate, but homologous, 8-base AU-sequences within the 3'-nontranslated region of the GDH mRNA. The apparent binding activity of z-crystallin is increased significantly during onset of metabolic acidosis. Thus, increased binding of z-crystallin may initiate the pH-responsive stabilization of the two mRNAs.
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PMID:Role of mitochondrial glutaminase in rat renal glutamine metabolism. 1153 99

The metabolic cross-talk associated with re-assimilation of photorespiratory NH4+ was analysed in transformed tobacco (Nicotiana tabacum L.) plants with low activities of ferredoxin-dependent glutamine-alpha-ketoglutarate aminotransferase (Fd-GOGAT; EC 1.4.7.1). Amounts of ribulose-1,5-bisphosphate carboxylase-oxygenase (Rubisco; EC 4.1.1.39) protein and Rubisco transcripts were similar in all lines whether photorespiration rates were low (4,000 microl l(-1) CO2) or high (air). Leaf sucrose, hexose and starch contents were similar in all lines. In contrast, there was evidence that anaplerotic carbon flow was stimulated in the transformed lines with less than 60% Fd-GOGAT, since phospho enolpyruvate carboxylase (PEPc) activity and (PEPc) protein were increased. A strong positive correlation between leaf PEPc activity and glutamine accumulation was observed, suggesting that the increase in PEPc was related to the accumulation of glutamine. A modest stimulation of total NADP-isocitrate dehydrogenase (ICDH; EC 1.1.1.42) activity was also observed in the transformed lines with less than 60% Fd-GOGAT. This was accompanied by increases in both the cytosolic ICDH and mitochondrial NAD-isocitrate dehydrogenases (IDH; EC 1.1.1.41). IDH protein was also increased in the transformed plants with low Fd-GOGAT, suggesting that both IDH and ICDH are involved in the production of carbon skeletons (and ultimately alpha-ketoglutarate) necessary for the re-assimilation of NH4+. In contrast, PEPc, ICDH and IDH transcripts were similar in all lines. The aminating (but not the de-aminating) activity of NAD(H)-glutamate dehydrogenase (NAD(H)-GDH; EC 1.4.1.2) was greatly increased in plants with less than 60% of Fd-GOGAT after transfer to air. The data confirm that NH4+ or glutamine are involved in signalling, leading to modified gene expression and enzyme activity required for enhanced production of the C skeletons, to accommodate increases in the assimilation of photorespiratory NH4+. In addition, we provide the first demonstration of a compensatory role for NAD(H)-GDH in stabilising the leaf glutamic acid pool when Fd-GOGAT becomes limiting.
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PMID:Photorespiration-dependent increases in phospho enolpyruvate carboxylase, isocitrate dehydrogenase and glutamate dehydrogenase in transformed tobacco plants deficient in ferredoxin-dependent glutamine-alpha-ketoglutarate aminotransferase. 1194 64

It has traditionally been thought that animals can utilize ammonia for amino acid biosynthesis, and that for them some amino acids are nutritionally nonessential. Presumably this idea originates from the notions of Schoenheimer (G. L. Foster et al. [1939] J. Biol. Chem. 127, 319-327) and of Rose (W. C. Rose et al. [1948] J. Biol. Chem. 176, 753-762), which we question for the following reasons. First, Schoenheimer's experiments only showed the incorporation of ammonia into amino acids. This may occur simply as an exchange between ammonia and the alpha-amino group of endogenous amino acids and reflects the enzymatic properties of glutamate dehydrogenase, which is a reversible enzyme. Second, Rose's nutritional experiments were concerned with whether carbon skeletons of particular amino acids can (nonessential) or cannot (essential) be synthesized from common intermediates of carbohydrate metabolism. We propose that mammals, living as they do at the top of the food web, are absolutely dependent directly or indirectly on higher plants and microorganisms for preformed alpha-amino nitrogen per se and that the first joining of C- and N-atoms to make glutamate constitutes a basic anabolic system in nature after the fixation of CO2 and N2.
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PMID:Animals are dependent on preformed alpha-amino nitrogen as an essential nutrient. 1204 95

Biocatalytic processes were used to prepare chiral intermediates for pharmaceuticals. These include the following processes. Enzymatic synthesis of [4S-(4a,7a,10ab)]1-octahydro-5-oxo-4-[[(phenylmethoxy) carbonyl]amino]-7H-pyrido-[2,1-b] [1,3]thiazepine-7-carboxylic acid methyl ester (BMS-199541-01), a key chiral intermediate for synthesis of a new vasopeptidase inhibitor. Enzymatic oxidation of the epsilon-amino group of lysine in dipeptide dimer N2-[N[[(phenylmethoxy)carbonyl] L-homocysteinyl] L-lysine)1,1-disulfide (BMS-201391-01) to produce BMS-199541-01 using a novel L-lysine epsilon-aminotransferase from S. paucimobilis SC16113 was demonstrated. This enzyme was overexpressed in E. coli, and a process was developed using recombinant enzyme. The aminotransferase reaction required alpha-ketoglutarate as the amine acceptor. Glutamate formed during this reaction was recycled back to alpha-ketoglutarate by glutamate oxidase from S. noursei SC6007. Synthesis and enzymatic conversion of 2-keto-6-hydroxyhexanoic acid 5 to L-6-hydroxy norleucine 4 was demonstrated by reductive amination using beef liver glutamate dehydrogenase. To avoid the lengthy chemical synthesis of ketoacid 5, a second route was developed to prepare the ketoacid by treatment of racemic 6-hydroxy norleucine (readily available from hydrolysis of 5-(4-hydroxybutyl) hydantoin, 6) with D-amino acid oxidase from porcine kidney or T. variabilis followed by reductive amination to convert the mixture to L-6-hydroxynorleucine in 98% yield and 99% enantiomeric excess. Enzymatic synthesis of (S)-2-amino-5-(1,3-dioxolan-2-yl)-pentanoic acid (allysine ethylene acetal, 7), one of three building blocks used for synthesis of a vasopeptidase inhibitor, was demonstrated using phenylalanine dehydrogenase from T. intermedius. The reaction requires ammonia and NADH. NAD produced during the reaction was recycled to NADH by oxidation of formate to CO2 using formate dehydrogenase. Efficient synthesis of chiral intermediates required for total chemical synthesis of a beta 3 receptor agonist was demonstrated. These include: (a) microbial reduction of 4-benzyloxy-3-methanesulfonylamino-2'-bromoacetophenone 9 to corresponding (R)-alcohol 10 by S. paucimobilis SC16113, (b) enzymatic resolution of racemic alpha-methyl phenylalanine amide 11 and alpha-methyl-4-hydroxyphenylalanine amide 13 by amidase from M. neoaurum ATCC 25795 to prepare corresponding (S)-amino acids 12 and 14, and (c) asymmetric hydrolysis of methyl-(4-methoxyphenyl)-propanedioic acid ethyl diester 15 to corresponding (S)-monoester 16 by pig liver esterase. (S)[1-(acetoxyl)-4-(3-phenyl)butyl]phosphonic acid diethyl ester 21, a key chiral intermediate required for total chemical synthesis of BMS-188494 (an anticholesterol drug) was prepared by stereoselective acetylation of racemic [1-(hydroxy)-4-(3-phenyl)butyl]phosphonic acid diethyl ester 22 using G. candidum lipase. Lipase-catalyzed stereoselective acetylation of racemic 7-[N,N'-bis-(benzyloxy-carbonyl)N-(guanidinoheptanoyl)]-alpha-hydroxy-glycine 24 to corresponding S-(-)-acetate 25 was demonstrated. S-(-)-acetate 25 is a key intermediate for total chemical synthesis of (-)-15-deoxyspergualin 23, an immunosuppressive agent and antitumor antibiotic. Stereoselective microbial reduction of (1S)[3-chloro-2-oxo-1-(phenyl-methyl)propyl] carbamic acid, 1,1-dimethyl-ethyl ester 26 to corresponding chiral alcohol 27a (a key chiral intermediate for HIV protease inhibitors) was also demonstrated. Stereospecific enzymatic hydrolysis of racemic epoxide RS-1-[2',3'-dihydro benzo[b]furan-4'-yl]-1,2-oxirane 29 the corresponding R-diol 30 and unreacted chiral S-epoxide 28 was demonstrated using R. glutinis and A. niger. Dynamic resolution of racemic diol RS-1-[2',3'-dihydrobenzo[b]furan-4'-yl]-ethane-1,2-diol 32 to corresponding S-diol S-1-[2',3'-dihydrobenzo[b]furan-4'-yl]-ethane-1,2-diol 31 was demonstrated using C. boidinii and P. methanolica. Chiral (S)-epoxide 28 and (S)-diol 31 are key intermediates for a new prospective circadian modulator drug. Enzymatic resolution of racemic 2-pentanol and 2-heptanol by lipase B from Candida antarctica was demonstrated. S-(+)-2-pentanol is a key chiral intermediate required for synthesis of anti-Alzheimer's drugs.
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PMID:Microbial/enzymatic synthesis of chiral drug intermediates. 1287 94

Nitrogen metabolism is not only one of the basic processes of plant physiology, but also one of the important parts of global chemical cycle. Plant nitrogen assimilation directly takes part in the synthesis and conversion of amino acid through the reduction of nitrate. During this stage, some key enzymes, e.g., nitrate reductase (NR), glutamine synthetase (GS), glutamate dehydrogenase (GDH), glutamine synthase (GOGAT), aspargine synthetase (AS), and asparate aminotransferase (AspAT) participate these processes. The protein is assimilated in plant cell through amino acid, and becomes a part of plant organism through modifying, classifying, transporting and storing processes, etc. The nitrogen metabolism is associated with carbonic metabolism through key enzyme regulations and the conversion of products, which consists of basic life process. Among these amino acids in plant cell, glutamic acid (Glu), glutamine (Gln), aspartic acid (Asp) and asparagines (Asn), etc., play a key role, which regulates their conversion each other and their contents in the plant cell through regulating formation and activity of those key enzymes. Environmental factors also affect the conversion and recycle of the key amino acids through regulating gene expression of the key enzymes and their activities. Nitrate and light intensity positively regulate the gene transcription of NR, but ammonium ions and Glu, Gln do the negative way. Water deficit is a very serious constraint on N2 fixation rate and soybean (Glycine max Merr.) grain yield, in which, ureide accumulation and degradation under water deficit appear to be the key issues of feedback mechanism on nitrogen fixation. Water stress decreases NR activity, but increases proteinase activity, and thus, they regulate plant nitrogen metabolism, although there are some different effects among species and cultivars. Water stress also decreases plant tissue protein content, ratio of protein and amino acid, and reduces the absorption of amino acid by plant. On the contrary, soil flooding decreases the content and accumulation amount of root nitrogen in winter wheat by 11.9% from booting to flowering stages and 39.1% during grain filling stage, and reduces the ratio of carbon and nitrogen by 79.6%. The results misadjust the metabolism between carbon and nitrogen, and result in the end of the root growth. Elevated CO2 level could decrease plant leaf nitrogen content under well-watered condition, but almost maintain stable under water deficit condition. The radiation of UV-B significantly reduces the partitioning coefficient and synthetic rate of Rubisco, which significantly decreases the photosynthetic rate. This paper reviewed the pathway of plant nitrogen assimilation, characteristics of key enzymes and their regulating mechanisms with picturing the regulating mode of NR, and described the signal sensing and conduct of plant nitrogen metabolism and the formation, transportation, storage and degradation of plant cell protein with picturing the schedule of protein transport of membrane system in plant cell. Seven key tasks are emphasized in this paper in terms of the review on the effects and mechanisms of key ecological factors including water stress on plant nitrogen metabolism. They are: 1) the absorption mechanism of plant based on different nitrogen sources and environmental regulations, 2) the localization and compartmentalization of the key enzymes of nitrogen mechanism in plant cell, 3) the gene and environmental regulating model and their relationships in various key enzymes of nitrogen metabolism, 4) the function of main cell organs and their responses to environmental factors in nitrogen metabolism process, 5) physiological and chemical mechanism of nitrogen and the relationship between the mechanism and protein formation during crop grain filling, 6) improving gene structure of special species or cultivars using gene engineering methods to enhance the resistance to environmental factor stress and the efficiency of absorption and transportation of nitrogen, and 7) the mechanism of natural nitrogen cycle and its response to human activity disturbance.
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PMID:[Research advance in nitrogen metabolism of plant and its environmental regulation]. 1522 8

We undertook the study of the use of glutamine (Gln) as the source of carbon and energy by Rhizobium etli. Tn5-induced mutagenesis allowed us to identify several genes required for Gln utilization, including those coding for two broad-range amino acid transporters and a glutamate dehydrogenase. The isolated mutants were characterized by the analysis of their capacity i) to grow on different media, ii) to transport Gln (uptake assays), and iii) to utilize Gln as the C energy source (CO2 production from Gln). We show that Gln is degraded through the citric acid cycle and that its utilization as the sole C source is related to a change in the bacterial cell shape (from bacillary to coccoid form) and a high susceptibility to a thiol oxidative insult. Both these data and the analysis of ntr-dependent promoters suggested that Gln-grown bacteria are under a condition of C starvation and N sufficiency, and as expected, the addition of glucose counteracted the morphological change and increased both the bacterial growth rate and their resistance to oxidative stress. Finally, a nodulation analysis indicates that the genes involved in Gln transport and degradation are dispensable for the bacterial ability to induce and invade developing nodules, whereas those involved in gluconeogenesis and nucleotide biosynthesis are strictly required.
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PMID:Glutamine utilization by Rhizobium etli. 1524 66

The estimation of the intracellular fluxes of mammalian cells using only the mass balances of the relevant metabolites is not possible because the set of linear equations defined by these mass balances is underdetermined. Either additional experimental flux data or additional theoretical constraints are required to find one unique flux distribution out of the solution space that is bound by the mass balances. Here, a method is developed using the latter approach. The uptake and production rates of amino acids, glucose, lactate, O(2), CO(2), NH(4), MAB, and the intracellular amino acid pools have been determined for two different steady-states. The cellular composition {total protein and protein composition, total lipids and fatty acid distribution, total carbohydrates, DNA and RNA} has been measured to calculate the requirements for biosynthesis. It is shown to be essential to determine the uptake/production rates of ammonia and either carbon dioxide or oxygen. In mammalian cells these are cometabolites of cyclic metabolic pathways. The flux distribution that is found using the Euclidean minimum norm as the additional theoretical constraint and taking either the CO(2) or the NAD(P)H mass balance into account is shown to be in agreement with the measured O(2) and CO(2) metabolic rates.The metabolic fluxes in hybridoma cells in continuous culture at a specific growth rate of 0.83 day(-1) are estimated for a medium with (optimal medium) and without (suboptimal medium) Primatone RL, an enzymatic hydrolysate of animal tissue that causes a more than twofold increase in cell density. It is concluded that (i)The majority of the consumed glucose (>90%) is channeled through the pentose-phosphate pathway in rapidly proliferating cells.(ii)Pyruvate oxidation and tricarboxylic acid (TCA) cycle activity are relatively low, i.e., 8% of the glucose uptake in suboptimal and 14% in optimal medium, respectively. Under both conditions, only a small fraction of pyruvate is further oxidized to CO(2).(iii)The flux from glutamate to alpha-ketoglutarate (catalyzed by glutamate dehydrogenase) is almost zero in medium with and even slightly reversed in medium without Primatone RL. Almost all glutamate enters the TCA cycle due to the action of transaminases.(iv)Transhydrogenation plays a significant role in hybridoma cells under our experimental conditions. NADPH is produced at relatively high rates (11 x 10(-12) to 13 x 10(-12) mol . cell(-1) . day(-1)) compared to other fluxes in both culture media.
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PMID:Metabolic flux analysis of hybridoma cells in different culture media using mass balances. 1862 58

The aim of the study was to investigate protein intake in groups of different physical activity. The research was undertaken over a group of young people of different physical activity (age group 15-18 years) including ballet dancers, karate fighters, cross runners as well as adolescents of average physical activity (female and male). The investigation was performed in two series. The first--before intense exercise training and the second--after intense exercise training. In control group there was only one series. Urea was estimated by using urease which converts urea into ammonia, CO2 and glutamic dehydrogenase reaction via measurements of ammonia derived from urea. The amounts of urea were applied for counting quantity of consumed proteins. In the physically active groups the protein intake was too low in comparison to required.
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PMID:[Protein intake in selected youth groups of different physical activity and requirements for athletes]. 1909 82

Hydrogenobacter thermophilus TK-6 is a thermophilic, chemolithoautotrophic, hydrogen-oxidizing bacterium that fixes carbon dioxide via the reductive tricarboxylic acid (rTCA) cycle. 2-Oxoglutarate:ferredoxin oxidoreductase (OGOR) is the key enzyme in this cycle that fixes carbon dioxide. The genome of strain TK-6 encodes at least two distinct OGOR enzymes, termed For and Kor. We report here a method for measuring the carboxylation of succinyl-CoA catalyzed by OGORs. The method involves the in vitro coupling of OGOR with ferredoxin and pyruvate:ferredoxin oxidoreductase from strain TK-6, and glutamate dehydrogenase from Sulfolobus tokodaii. Using this method, we determined both the apparent maximum velocities and the K (m) values of For and Kor for the carboxylation of succinyl-CoA. This is the first reported kinetic analysis of carbon fixation catalyzed by OGOR enzymes from the rTCA cycle.
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PMID:Carboxylation reaction catalyzed by 2-oxoglutarate:ferredoxin oxidoreductases from Hydrogenobacter thermophilus. 1989 84


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