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drug target
since glutamine synthetase is the first metabolic enzyme involved in Trypanosoma cruzi evasion from the parasitophorous vacuole it is a potential target for designing anti-Trypanosoma cruzi drugs
drug target
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since glutamine synthetase is the first metabolic enzyme involved in Trypanosoma cruzi evasion from the parasitophorous vacuole it is a potential target for designing anti-Trypanosoma cruzi drugs
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evolution
glutamine synthetase (GS), a key enzyme in plant nitrogen metabolism, is encoded by a small family of highly homologous nuclear genes that produce cytosolic (GS1) and plastidic (GS2) isoforms. Compared to GS1, GS2 proteins have two extension peptides, one at the N- and the other at the C-terminus, which show a high degree of conservation among plant species
evolution
two GS isoforms are encoded in the genome of higher plants: the cytosolic Gln synthetase isoform (GS1) and the chloroplastic Gln synthetase isoform (GS2). GS2 is encoded by a single gene (Gln-2), whereas GS1 is encoded by a multigene family, suggesting a complex role of GS1 with respect to plant N assimilation
evolution
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Unigene0016999 and Unigene0017002 belong to isozyme GSI, while Unigene0015608, Unigene0022741, and Unigene0002184 belong to isozyme GSII, and Unigene0002194 belongs to isozyme GSIII, sequence comparisons and phylogenetic tree, overview
malfunction
OsGS1;2 homozygously inserted mutants show severe reduction in active tiller number and hence panicle number at harvest. The mutants show marked reductions in contents of glutamine, glutamate, asparagine and aspartate, but an increase in free ammonium ions compared to the wild-type
malfunction
a gln1-1:gln1-2 double mutant shows impairment of seed germination and seedling establishment, phenotype, overview
malfunction
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astrocytes enable the proliferation of GS-negative LN18 iRFP4 cells without Gln supplementation
malfunction
depletion of the enzyme in Hep-3B cells by transduction with two independent shRNAs reduces LC3-II formation. Conversely, exogenous enzyme overexpression increases autophagic activity in SK-Hep1 cells. Glutamine synthetase (GS) overexpression significantly increases sorafenib sensitivity in hepatocellular carcinoma cells
malfunction
enzyme mutants, single mutant gln1-2 and gln1-1:gln1-2 double mutant, show impairment of seed germination and seedling establishment. The negative effect of Gln1-2 deficiency, causing slower seedling development in the mutants, is associated with reduced N remobilization from the cotyledons and can be fully alleviated by exogenous N supply. Phenotypes, overview
malfunction
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the total capacity of the enzyme-mediated ligation of free ammonium and glutamate to form glutamine in the leaves of maize plants is not impaired upon severe magnesium starvation. The total GS-mediated primary or secondary assimilation of free NH4+ is not a limiting enzymatic reaction under Mg-deficiency and thus cannot be accountable for the observed restriction of plant growth and productivity in Mg-deficient maize, phenotype, overview
metabolism
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leaves of seedling grown in light for seven days contain about twofold higher glutamine synthetase activity than etiolated leaves. In both light and dark grown seedlings, total glutamine synthetase, isoforms GS1 and GS2 activities decline with plant age with more pronounced effect in leaves of etiolated seedlings. Isoform GS2 declines at a much faster rate than isoform GS1. Exposure of etiolated seedlings to light markedly enhances GS1 and GS2 activity, which is not affected by cycloheximide. Photosynthetic inhibitor dichlorophenyl dimethyl urea inhibits light dependent appearance of glutamine synthetase
metabolism
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presence of only one glutathione synthetase inactivation factor, 7A, encoded by open reading frame asl2329, gifA. Following addition of ammonium, expression of gifA is derepressed, leading to the synthesis of IF7A, and consequently, glutathione synthetase is inactivated. Upon ammonium removal, the glutathione synthetase activity returns to the initial level and IF7A becomes undetectable. Anabaena glutathione synthetase is not inactivated by Synechocystis IFs. In an Anabaena strain expressing a second inactivating factor, containing the amino-terminal part of IF17 from Synechocystis fused to IF7A, glutathione synthetase inactivation is more effective than that in the wild-ype and resembles that observed in Synechocystis
metabolism
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upon exposure to nitrogen limitation,GS activity increases significantly within 0.5 hrs and continues to increase significantly after 1 hr of nitrogen starvation to reach a final activity at 4 hrs that is approximately 2.5 fold greater than at zero hours. When an ammonium pulse is applied, GS activity decreases significantly within 1 hr of exposure to nitrogen excess
metabolism
glutamine synthetase plays essential roles in nitrogen metabolism
metabolism
glutamine synthetase is a key enzyme in plant nitrogen metabolism
metabolism
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glutamine-starved GBM cells feed on astrocyte-derived glutamine. Only astrocytes demonstrate no net Gln consumption but rather, rapid Glu uptake, in line with the expression of excitatory amino acids transporters (EAAT) in this cell type. Under Gln starvation, Glu consumption is unaffected and paralleled by an equimolar net Gln efflux. The absence of Gln in the medium reduces intracellular Gln, but not Glu. Only 30-40% of both intracellular Glu and Gln are glucose-derived. Astrocytes maintain about 30% of the control level of intracellular Gln under Gln starvation, fitting with high enzyme expression. Astrocyte-derived Gln is the growth-supporting factor for Gln-starved glioblastoma cells
metabolism
the enzyme catalyzes the ATP-dependent synthesis of L-glutamine from glutamate and ammonia. GlnA1 is also involved in the synthesis of poly-L-glutamate/glutamine for the cell wall of pathogenic mycobacteria
metabolism
the glutamine synthetase/glutamate synthase cycle is considered as the major pathway for ammonium assimilation and regulation of nitrogen metabolism in higher plants
metabolism
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presence of only one glutathione synthetase inactivation factor, 7A, encoded by open reading frame asl2329, gifA. Following addition of ammonium, expression of gifA is derepressed, leading to the synthesis of IF7A, and consequently, glutathione synthetase is inactivated. Upon ammonium removal, the glutathione synthetase activity returns to the initial level and IF7A becomes undetectable. Anabaena glutathione synthetase is not inactivated by Synechocystis IFs. In an Anabaena strain expressing a second inactivating factor, containing the amino-terminal part of IF17 from Synechocystis fused to IF7A, glutathione synthetase inactivation is more effective than that in the wild-ype and resembles that observed in Synechocystis
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metabolism
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glutamine synthetase plays essential roles in nitrogen metabolism
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metabolism
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the enzyme catalyzes the ATP-dependent synthesis of L-glutamine from glutamate and ammonia. GlnA1 is also involved in the synthesis of poly-L-glutamate/glutamine for the cell wall of pathogenic mycobacteria
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physiological function
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glutathione synthetase binds to transcription factor TnrA in its feedback-inhibited form, and also in its non-feedback-inhibited form, although less efficiently. TnrA forms either a stable soluble complex with GlnK in the absence of transmembrane ammonium transporter AmtB, or constitutively binds to glutathione synthetase in the absence of regulatuor GlnK. In vitro, the TnrA C-terminus is responsible for interactions with either glutathione synthetase or GlnK, and this region appears also to mediate proteolysis, suggesting that binding of GlnK or glutathione synthetase protects TnrA from degradation
physiological function
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mice in which glutamine synthetase is selectively but completely eliminated from striated muscle are healthy and fertile. A 3-fold higher escape of ammonia reveals the absence of glutamine synthetase in muscle. After 20 h of fasting, glutamine synthetase-KO mice are not able to mount the 4fold increase in glutamine production across the hindquarter that is observed in control mice. Instead, muscle ammonia production is 5fold higher than in control mice. The fasting-induced metabolic changes are transient and return to fed levels at 36 h of fasting. Glucose consumption and lactate and ketone-body production are similar in glutamine synthetase-KO and control mice. Challenging glutamine synthetase-KO and control mice with intravenous ammonia in stepwise increments reveals that normal muscles can detoxify 2.5 mol ammonia/g muscle h in a muscle glutamine synthetase-dependent manner, with simultaneous accumulation of urea, whereas glutamine synthetase-KO mice respond with accumulation of glutamine and other amino acids, but not urea
physiological function
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rice mutant lacking OsGS1-1 exhibits severe retardation of shoot growth in the presence of ammonium compared with the wild-type. Overaccumulation of free ammonium in the leaf sheath and roots of the mutant indicates the importance of OsGS1-1 for ammonium assimilation in both organs. The mutant line displays an imbalance in levels of sugars, amino acids and metabolites in the tricarboxylic acid cycle, and overaccumulation of secondary metabolites, particularly in the roots under a continuous supply of ammonium. Presence of mutant-specific networks between tryptamine andother primary metabolites in the roots
physiological function
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study on glnA-1 mutant that produces reduced levels of glutamine synthetase. The mutant is able to grow in enriched 7H9 medium without glutamine supplementation.The glnA-1 strain contains no detectable poly-alpha-L-glutamine in the cell walls and shows marked sensitivity to different chemical and physical stresses such as lysozyme, SDS and sonication. The sensitivity of the mutant to antitubercular drugs, rifampicin and D-cycloserine, is also increased. The glnA-1 strain infects THP-1 cells with reduced efficiency and is also attenuated for growth in macrophages. A Mycobacterium smegmatis strain containing the Mycobacterium bovis glnA-1 gene survives longer in THP-1 cells than the wild-type strain and also produces cell wall-associated poly-alpha-L-glutamine. The mutant is not able to replicate in the organs of BALB/c mice and is cleared within 4-6 weeks of infection. Disruption of the glnA-1 gene adversely affects biofilm formation on polystyrene surfaces
physiological function
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the C-terminal domain peptide of nod26, a major intrinsic protein that constitutes the major protein component on the symbiosome membrane of N2-fixing soybean nodules, interacts with cytosolic glutamine synthetase GS1beta1. Recombinant soybean GS1beta1 binds the nod26 C-terminal domain with a 1:1 stoichiometry. GS1beta1 also binds to isolated symbiosome membranes, and this binding can be blocked by preincubation with the C-terminal peptide of nod26. In vivo the four cytosolic GS isoforms expressed in soybean nodules interact with full-length nod26
physiological function
hyperthermophilic archaea do not utilize glutamine synthetase predominantly for ammonia assimilation (the major pathway for ammonia assimilation is through glutamate dehydrogenase). The enzyme might play some role in ammonia assimilation under ammonia-starvation conditions
physiological function
glutamine synthetase catalyzes the synthesis of glutamine, providing nitrogen for the production of purines, pyrimidines, amino acids, and other compounds required in many pivotal cellular events. The enzyme is important in the development of the schistosome
physiological function
glutamine synthetase is a key enzyme for root nodule metabolism, and is a molecular target of nitric oxide in root nodules of Medicago truncatula and is regulated by tyrosine nitration. NO-mediated GS posttranslational inactivation is related to metabolite channeling to boost the nodule antioxidant defenses in response to NO
physiological function
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glutamine synthetase is the only human enzyme responsible for the de novo synthesis of glutamine, catalyzes the reaction of glutamate and ammonia. The enzyme influences sperm motility in mammals
physiological function
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glutamine synthetase plays a particularly important role in nitrogen metabolism and is the principal source of N for protein and nucleic acid synthesis
physiological function
isozyme OsGS1;1 in the roots is unable to compensate for isozyme OsGS1;2 functions
physiological function
isozyme OsGS1;2 is important in the primary assimilation of ammonium ions taken up by rice roots. Isozyme OsGS1;1 is unable to compensate for isozyme OsGS1;2 functions in roots
physiological function
the enzyme catalyzes the ATP-dependent assimilation of ammonium into glutamate to yield glutamine, which is then used for the biosynthesis of essentially all nitrogenous compounds. Effect of water deprivation varies with variety, degree and duration of stress
physiological function
the enzyme catalyzes the ATP-dependent assimilation of ammonium into glutamate to yield glutamine, which is then used for the biosynthesis of essentially all nitrogenous compounds. Gene OsGS1;1 expression is differently regulated by drought stresss in the two rice Oryza sativa varieties, effect of water deprivation varies with variety, degree and duration of stress
physiological function
the enzyme glutamine synthetase plays an important role in the nitrogen metabolism of fish and in detoxifying ammonia, fish either decrease the production of ammonia, maintain/increase its excretion, or convert ammonia to less toxic products such as glutamine
physiological function
the enzyme is indispensable under excess ammonium conditions. It is required for the resistance of the organism to ammonium accumulation and evasion of the parasitophorous vacuole during host-cell infection. The enzyme contributes to the management of excess ammonium and uses it to form the amino acid glutamine. During its life cycle, the parasite invades mammalian host cells and transiently becomes enclosed in a tight vacuole, where it differentiates into the amastigote, an amino acid consumer stage. Amastigotes must escape from the vacuole into the host-cell cytoplasm to initiate intracellular replication. The inhibition of Trypanosoma cruzi glutamine synthetase aborts parasite evasion from the vacuole. The enzyme contributes to the control of ammonium produced by parasite metabolism, as ammonium increases the internal pH of the parasitophorous vacuole, making the enzymes for the Trypanosoma cruzi evasion process non-functional
physiological function
ammonium is incorporated into carbon skeletons by the sequential action of glutamine synthetase (GS) and glutamate synthase (GOGAT) in cyanobacteria. The activity of Synechocystis sp. PCC 6803 GS type I enzyme is controlled by protein-protein interactions with two intrinsically disordered inactivating factors (IFs): the 65-residue (IF7) and the 149-residue one (IF17), NMR sequence analysis and structure study, overview. The electrostatic-determined binding does not follow a kinetic two-state model, the binding is not diffusion-limited
physiological function
Gln synthetase catalyzes the assimilation of ammonium into Gln and constitutes as such a central component of the N assimilatory pathway in plants. GS2 is the predominant GS isoform in leaves of vegetatively growing plants. In shoots, both GS1 and GS2 contribute to ammonium assimilation into Gln
physiological function
Gln synthetase catalyzes the assimilation of ammonium into Gln and constitutes as such a central component of the N assimilatory pathway in plants. In shoots, both GS1 and GS2 contribute to ammonium assimilation into Gln
physiological function
Gln synthetase catalyzes the assimilation of ammonium into Gln and constitutes as such a central component of the N assimilatory pathway in plants. In shoots, both GS1 and GS2 contribute to ammonium assimilation into Gln. Isozyme Gln-1;2 is essential for ammonium assimilation and amino acid synthesis. Gln-1;2 is the main isozyme contributing to shoot GS1 activity in vegetative growth stages and can be up-regulated to relieve ammonium toxicity
physiological function
glutamine synthetase catalyzes the formation of glutamine from glutamate in the presence of NH4+, ATP, and metal cations. The reaction is the rate-limiting step in the control of N-assimilation and N-recycling during growth and development of plants
physiological function
glutamine synthetase in nodule cytosol plays a major role in the assimilation of the ammonium produced by biological nitrogen fixation
physiological function
glutamine synthetase is an important enzyme that catalyzes the conversion of L-glutamate into L-glutamine and ammonia in an energy dependent reaction with the simultaneous hydrolysis of ATP to ADP. In the cellular system, the enzyme plays an important role in nitrogen metabolism under ammonia-limiting conditions
physiological function
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glutamine synthetase is one of the key enzymes in nitrogen assimilation, ligating-free ammonium to glutamate to form glutamine and it is therefore crucial for plant growth and productivity
physiological function
glutamine synthetase-mediated autophagy explains the high sensitivity of beta-catenin-active hepatocellular carcinoma cells to sorafenib. beta-Catenin regulates the expression of glutamine synthetase and triggers a series of metabolic changes leading to induction of autophagy in hepatocellular carcinoma cells. Autophagy in beta-catenin-active Hep-3B and Hep-G2 cells is mediated by glutamine synthetase, as silencing of glutamine synthetase significantly reduced autophagic activity
physiological function
specific roles of the individual GS1 isogenes with respect to nitrogen remobilization, early seedling vigour, and final seed productivity. Isozyme Gln1-2 plays an important role in N remobilization for both seedling establishment and seed production in Arabidopsis thaliana
physiological function
specific roles of the individual GS1 isogenes with respect to nitrogen remobilization, early seedling vigour, and final seed productivity. Isozymes Gln1-1 and Gln1-2 play specific roles in seed germination and seedling establishment in Arabidopsis thaliana
physiological function
the enzyme catalyses the ATP-dependent condensation of ammonium and L-glutamate, thus forming L-glutamine, ADP, phosphate and a proton. The enzyme is highly expressed and essential for the growth of the bacteria both in vitro and in vivo. The Mycobacterium tuberculosis enzyme plays an important role in cell wall biosynthesis, specifically via the production of a poly-L-glutamate-glutamine component found exclusively in pathogenic mycobacteria. Extracellular Mycobacterium tuberculosis enzyme may also affect pH modulation in phagosomes and consequently prevent phagosome-lysosome fusion
physiological function
the enzyme catalyzes the ATP-dependent synthesis of L-glutamine from glutamate and ammonia. GlnA1 is also involved in the synthesis of poly-L-glutamate/glutamine for the cell wall of pathogenic mycobacteria
physiological function
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the rate-limiting step in photorespiration is the reassimilation of ammonia catalyzed by chloroplastic glutamine synthetase isozyme 2 (GS2). In plants, GS2 together with ferredoxin-dependent glutamate synthase (Fd-GOGAT) plays a major role in re-assimilation of ammonium liberated in mitochondria by the glycine decarboxylase, in the pathway known as glutamine synthetase/glutamate synthase (GS/GOGAT) cycle in chloroplasts. The product of this cycle, glutamate, is required for one of the peroxisomal transamination reactions
physiological function
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glutamine synthetase is an important enzyme that catalyzes the conversion of L-glutamate into L-glutamine and ammonia in an energy dependent reaction with the simultaneous hydrolysis of ATP to ADP. In the cellular system, the enzyme plays an important role in nitrogen metabolism under ammonia-limiting conditions
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physiological function
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glutamine synthetase plays a particularly important role in nitrogen metabolism and is the principal source of N for protein and nucleic acid synthesis
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physiological function
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hyperthermophilic archaea do not utilize glutamine synthetase predominantly for ammonia assimilation (the major pathway for ammonia assimilation is through glutamate dehydrogenase). The enzyme might play some role in ammonia assimilation under ammonia-starvation conditions
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physiological function
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the enzyme is indispensable under excess ammonium conditions. It is required for the resistance of the organism to ammonium accumulation and evasion of the parasitophorous vacuole during host-cell infection. The enzyme contributes to the management of excess ammonium and uses it to form the amino acid glutamine. During its life cycle, the parasite invades mammalian host cells and transiently becomes enclosed in a tight vacuole, where it differentiates into the amastigote, an amino acid consumer stage. Amastigotes must escape from the vacuole into the host-cell cytoplasm to initiate intracellular replication. The inhibition of Trypanosoma cruzi glutamine synthetase aborts parasite evasion from the vacuole. The enzyme contributes to the control of ammonium produced by parasite metabolism, as ammonium increases the internal pH of the parasitophorous vacuole, making the enzymes for the Trypanosoma cruzi evasion process non-functional
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physiological function
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the enzyme catalyzes the ATP-dependent synthesis of L-glutamine from glutamate and ammonia. GlnA1 is also involved in the synthesis of poly-L-glutamate/glutamine for the cell wall of pathogenic mycobacteria
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physiological function
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the enzyme catalyses the ATP-dependent condensation of ammonium and L-glutamate, thus forming L-glutamine, ADP, phosphate and a proton. The enzyme is highly expressed and essential for the growth of the bacteria both in vitro and in vivo. The Mycobacterium tuberculosis enzyme plays an important role in cell wall biosynthesis, specifically via the production of a poly-L-glutamate-glutamine component found exclusively in pathogenic mycobacteria. Extracellular Mycobacterium tuberculosis enzyme may also affect pH modulation in phagosomes and consequently prevent phagosome-lysosome fusion
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additional information
the Bacillus subtilis enzyme undergoes dramatic intersubunit conformational alterations during formation of the transition state. Structure-function relationship, overview
additional information
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the Bacillus subtilis enzyme undergoes dramatic intersubunit conformational alterations during formation of the transition state. Structure-function relationship, overview
additional information
the enzyme sequence contains a classic beta-grasp domain and a catalytic domain of glutamine synthetase
additional information
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the enzyme sequence contains a classic beta-grasp domain and a catalytic domain of glutamine synthetase
additional information
enzyme structure-activity relationship, overview
additional information
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enzyme structure-activity relationship, overview
additional information
structure-function relationships of wild-type and mutant enzymes, ligand molecular docking, homology structure modeling using the crystal structure of the enzyme from Bacillus subtilis, PDB ID 4LNF, as a template, overview
additional information
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structure-function relationships of wild-type and mutant enzymes, ligand molecular docking, homology structure modeling using the crystal structure of the enzyme from Bacillus subtilis, PDB ID 4LNF, as a template, overview
additional information
the C-terminal extension peptide of plastid-located glutamine synthetase from Medicago truncatula is crucial for enzyme activity but needless for protein import into the plastids. The C-terminal extension peptide does not affect the solubility or the stability of the protein but likely the interaction of the enzyme with its substrates. The first 49 amino acids of the N-terminus are predicted to be the transit peptide, the sorting signal for targeting nucleus-encoded proteins to the plastids, which is cleaved during the import
additional information
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the C-terminal extension peptide of plastid-located glutamine synthetase from Medicago truncatula is crucial for enzyme activity but needless for protein import into the plastids. The C-terminal extension peptide does not affect the solubility or the stability of the protein but likely the interaction of the enzyme with its substrates. The first 49 amino acids of the N-terminus are predicted to be the transit peptide, the sorting signal for targeting nucleus-encoded proteins to the plastids, which is cleaved during the import
additional information
Val161 in GS1beta1 is the key residue responsible for the heat stability
additional information
Val161 in GS1beta1 is the key residue responsible for the heat stability
additional information
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structure-function relationships of wild-type and mutant enzymes, ligand molecular docking, homology structure modeling using the crystal structure of the enzyme from Bacillus subtilis, PDB ID 4LNF, as a template, overview
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additional information
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the Bacillus subtilis enzyme undergoes dramatic intersubunit conformational alterations during formation of the transition state. Structure-function relationship, overview
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additional information
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enzyme structure-activity relationship, overview
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