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Information on EC 6.3.1.2 - glutamine synthetase and Organism(s) Homo sapiens

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IUBMB Comments
Glutamine synthetase, which catalyses the incorporation of ammonium into glutamate, is a key enzyme of nitrogen metabolism found in all domains of life. Several types have been described, differing in their oligomeric structures and cofactor requirements.
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This record set is specific for:
Homo sapiens
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Word Map
The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
Synonyms
glutamine synthetase, gamma-glutamyl transferase, gs-ii, gsiii, taase, glna1, glna2, gln1;2, gln synthetase, gs(1), more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Chloroplast GS2
-
-
-
-
Clone lambda-GS28
-
-
-
-
Clone lambda-GS31
-
-
-
-
Clone lambda-GS8
-
-
-
-
Cytoplasmic GS3
-
-
-
-
Cytosolic GS1
-
-
-
-
gamma-glutamyl:ammonia ligase
-
-
Gln isozyme alpha
-
-
-
-
Gln isozyme beta
-
-
-
-
Gln isozyme gamma
-
-
-
-
Glutamate--ammonia ligase
-
-
-
-
glutamate-ammonia ligase
-
-
-
-
Glutamine synthetase
Glutamylhydroxamic synthetase
-
-
-
-
GS
-
-
-
-
GS(1)
-
-
-
-
GS1
-
-
-
-
GS107
-
-
-
-
GS112
-
-
-
-
GS117
-
-
-
-
GS122
-
-
-
-
GS2
-
-
-
-
GSI
-
-
-
-
GSII
-
-
-
-
GSIII
-
-
-
-
Isozyme delta
-
-
-
-
L-glutamate:ammonia ligase
-
-
L-Glutamine synthetase
-
-
-
-
N47/N48
-
-
-
-
S2205/S2287
-
-
-
-
Synthetase, glutamine
-
-
-
-
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
ATP + L-glutamate + NH3 = ADP + phosphate + L-glutamine
show the reaction diagram
reaction mechanism
SYSTEMATIC NAME
IUBMB Comments
L-glutamate:ammonia ligase (ADP-forming)
Glutamine synthetase, which catalyses the incorporation of ammonium into glutamate, is a key enzyme of nitrogen metabolism found in all domains of life. Several types have been described, differing in their oligomeric structures and cofactor requirements.
CAS REGISTRY NUMBER
COMMENTARY hide
9023-70-5
-
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
ATP + glutamate + NH4+
ADP + phosphate + L-glutamine
show the reaction diagram
ATP + L-Glu + NH4+
ADP + phosphate + L-Gln
show the reaction diagram
ATP + L-glutamate + NH3
ADP + phosphate + L-glutamine
show the reaction diagram
Gln + hydroxylamine + ADP
gamma-Glutamylhydroxamate + NH4+ + ?
show the reaction diagram
-
-
-
?
additional information
?
-
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
ATP + glutamate + NH4+
ADP + phosphate + L-glutamine
show the reaction diagram
ATP + L-glutamate + NH3
ADP + phosphate + L-glutamine
show the reaction diagram
additional information
?
-
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Li+
-
50 mM LiCl increases activity
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
Beta amyloid peptides
-
-
-
glucagon
-
slightly decreases enzyme activity
L-methionine sulfoximine
methionine sulfoxide
-
-
methionine sulfoximine
vitamin D
-
22% inhibition at 0.00001 mM, reduces dexamethasone induced increase in enzyme expression
additional information
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
beta-catenin
-
-
-
dexamethasone
-
rapid and marked increase in activity
Insulin
-
-
-
MK801
-
N-methyl-D-aspartate-type glutamate receptor antagonist, activates the enzyme and inhibits osteogenic differentiation of the rat bone marrow stem cells
trijodothyronine
-
only when cultures are simultaneously treated with growth hormone and dexamethasone
additional information
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
additional information
additional information
-
-
-
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
0.018
-
glutamine synthetase activity in MG-63 cells
0.022
-
glutamine synthetase activity in MG-63 cells in presence of MG-132
0.023
-
glutamine synthetase activity in MG-63 cells in presence of dexamethasone and MG-132
0.042
-
glutamine synthetase activity in MG-63 cells in presence of vitamin D
0.067
-
glutamine synthetase activity in MG-63 cells in presence of dexamethasone
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
6.8
-
assay at
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
37
-
assay at
pI VALUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
6
-
six isoforms with different pI
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
-
fetal
Manually annotated by BRENDA team
-
-
Manually annotated by BRENDA team
-
osteoblast-like cells
Manually annotated by BRENDA team
pancreatic endocrine tumor, solid and pseudopapillary neoplasms, the enzyme is overexpressed by 3-13fold in pancreatic tumors compared to healthy tissue, overview
Manually annotated by BRENDA team
-
-
Manually annotated by BRENDA team
-
post-acrosomal region of the perinuclear theca, a major cytoskeletal component of the sperm head
Manually annotated by BRENDA team
additional information
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
metabolism
-
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
physiological function
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION?
GLNA_HUMAN
373
0
42064
Swiss-Prot
other Location (Reliability: 3)
Q9NSP3_HUMAN
112
0
12637
TrEMBL
other Location (Reliability: 3)
A8YXX4_HUMAN
373
0
42064
TrEMBL
other Location (Reliability: 3)
A1L199_HUMAN
258
0
29143
TrEMBL
other Location (Reliability: 2)
A0A2R8YDT1_HUMAN
507
0
57174
TrEMBL
other Location (Reliability: 4)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
360000 - 400000
-
PAGE
44000
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
homooctamer
-
8 * 44000, SDS-PAGE
octamer
-
8 * 44000, SDS-PAGE, composed of three different types of subunits with isoelectric points ranging from 7.0-7.2
additional information
-
structure analysis, and comparison of mammalian, plant, and bacterial structures, overview
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
phosphoprotein
-
-
ubiquitinylation
-
-
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
two different enzyme complexes with: 1. phosphate, ADP, and manganese, and 2. a phosphorylated form of the inhibitor methionine sulfoximine, ADP and manganese. X-ray diffraction structure determination and analysis at resolutions of 2.05 A and 2.6 A, respectively, molecular replacement
-
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
56 - 71.5
-
the melting temperature Tm for the enzyme in absence of ligands is 56°C, glutamine or glutamate have no appreciable effect on the Tm. Addition of Mg2+ at concentrations of 500 mM causes an increase of about 2°C. The Tm increases by 4.1°C and 11.5°C upon the addition of 1 mM MnCl2 and 1 mM ATP, respectively. Addition of MnCl2 and ATP together increases the Tm of HsGS by 15.5°C
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
more than 50% loss of activity after one freeze/thaw cycle
-
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
from frozen and non-frozen tissue
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expression analysis
-
quantitative expression analysis
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
beta-catenin regulates the expression of glutamine synthetase
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
analysis
-
immunoassay that detects synthetase protein samples where the enzyme has been inactivated by repeated cycles of freezing and thawing, and in serum and cerebrospinal fluid where glutamine synthetase is undetectable by the enzyme activity assay
diagnostics
-
glutamine synthetase is a useful marker in tumour liver pathology, including hepatocellular adenomas and nodules in cirrhosis. Enzyme overexpression in focal nodular hyperplasia can be used as easy diagnostic tool in surgical pathology
drug development
-
the enzyme is a target for design of structure-based specific inhibitors
medicine
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Meister, A.
Glutamine synthetase from mammalian tissues
Methods Enzymol.
113
185-199
1985
Gallus gallus, Cricetulus griseus, Ovis aries, Homo sapiens, Mammalia, Rattus norvegicus, Sus scrofa
Manually annotated by BRENDA team
Haghighi, A.Z.; Maples, K.R.
On the mechanism of the inhibition of glutamine synthetase and creatine phosphokinase by methionine sulfoxide
J. Neurosci. Res.
43
107-111
1996
Homo sapiens
Manually annotated by BRENDA team
Tumani, H.; Shen, G.Q.; Peter, J.B.
Purification and immunocharacterization of human brain glutamine synthetase and its detection in cerebrospinal fluid and serum by a sandwich enzyme immunoassay
J. Immunol. Methods
188
155-163
1995
Homo sapiens
Manually annotated by BRENDA team
Shin, D.; Park, C.
N-terminal extension of canine glutamine synthetase created by splicing alters its enzymatic property
J. Biol. Chem.
279
1184-1190
2004
Canis lupus familiaris, Homo sapiens, Mus musculus
Manually annotated by BRENDA team
Boksha, I.S.; Tereshkina, E.B.; Burbaeva, G.S.
Glutamine synthetase and glutamine synthetase-like protein from human brain: purification and comparative characterization
J. Neurochem.
75
2574-2582
2000
Homo sapiens
Manually annotated by BRENDA team
Gebhardt, R.; Baldysiak-Figiel, A.; Kruegel, V.; Ueberham, E.; Gaunitz, F.
Hepatocellular expression of glutamine synthetase: an indicator of morphogen actions as master regulators of zonation in adult liver
Prog. Histochem. Cytochem.
41
201-266
2007
Bos taurus, Homo sapiens, Mus musculus, Rattus norvegicus
Manually annotated by BRENDA team
Vermeulen, T.; Goerg, B.; Vogl, T.; Wolf, M.; Varga, G.; Toutain, A.; Paul, R.; Schliess, F.; Haeussinger, D.; Haeberle, J.
Glutamine synthetase is essential for proliferation of fetal skin fibroblasts
Arch. Biochem. Biophys.
478
96-102
2008
Homo sapiens
Manually annotated by BRENDA team
Olkku, A.; Mahonen, A.
Wnt and steroid pathways control glutamate signalling by regulating glutamine synthetase activity in osteoblastic cells
Bone
43
483-493
2008
Homo sapiens
Manually annotated by BRENDA team
Eid, T.; Ghosh, A.; Wang, Y.; Beckstroem, H.; Zaveri, H.P.; Lee, T.S.; Lai, J.C.; Malthankar-Phatak, G.H.; de Lanerolle, N.C.
Recurrent seizures and brain pathology after inhibition of glutamine synthetase in the hippocampus in rats
Brain
131
2061-2070
2008
Homo sapiens, Rattus norvegicus
Manually annotated by BRENDA team
Eid, T.; Williamson, A.; Lee, T.S.; Petroff, O.A.; de Lanerolle, N.C.
Glutamate and astrocytes - key players in human mesial temporal lobe epilepsy?
Epilepsia
49 Suppl. 2
42-52
2008
Homo sapiens
Manually annotated by BRENDA team
Krajewski, W.W.; Collins, R.; Holmberg-Schiavone, L.; Jones, T.A.; Karlberg, T.; Mowbray, S.L.
Crystal structures of mammalian glutamine synthetases illustrate substrate-induced conformational changes and provide opportunities for drug and herbicide design
J. Mol. Biol.
375
217-228
2008
Homo sapiens, Canis lupus familiaris (Q8HZM5), Canis lupus familiaris
Manually annotated by BRENDA team
Watford, M.
Glutamine metabolism and function in relation to proline synthesis and the safety of glutamine and proline supplementation
J. Nutr.
138
2003S-2007S
2008
Homo sapiens
Manually annotated by BRENDA team
Bioulac-Sage, P.; Laumonier, H.; Rullier, A.; Cubel, G.; Laurent, C.; Zucman-Rossi, J.; Balabaud, C.
Over-expression of glutamine synthetase in focal nodular hyperplasia: a novel easy diagnostic tool in surgical pathology
Liver Int.
29
459-465
2008
Homo sapiens
Manually annotated by BRENDA team
Berlicki, L.
Inhibitors of glutamine synthetase and their potential application in medicine
Mini Rev. Med. Chem.
8
869-878
2008
Beta vulgaris, Bradyrhizobium japonicum, Chlorella sp., Columba sp., Escherichia coli, Ovis aries, Hordeum vulgare, Hordeum vulgare (P13564), Oryza sativa, Vigna radiata, Pisum sativum, Sorghum sp., Spinacia oleracea, Triticum aestivum, Zea mays, Senna obtusifolia, Rattus norvegicus (P09606), Salmonella enterica subsp. enterica serovar Typhimurium (P0A1P6), Bacillus subtilis (P12425), Homo sapiens (P15104), Mus musculus (P15105), Synechocystis sp. (P77961), Mycobacterium tuberculosis (P9WN39), Mycobacterium tuberculosis H37Rv (P9WN39)
Manually annotated by BRENDA team
Audard, V.; Cavard, C.; Richa, H.; Infante, M.; Couvelard, A.; Sauvanet, A.; Terris, B.; Paye, F.; Flejou, J.F.
Impaired E-cadherin expression and glutamine synthetase overexpression in solid pseudopapillary neoplasm of the pancreas
Pancreas
36
80-83
2008
Homo sapiens (P15104)
Manually annotated by BRENDA team
Long, J.; Wang, H.; Lang, Z.; Wang, T.; Long, M.; Wang, B.
Expression level of glutamine synthetase is increased in hepatocellular carcinoma and liver tissue with cirrhosis and chronic hepatitis B
Hepatol. Int.
5
698-706
2011
Homo sapiens
Manually annotated by BRENDA team
Francou, M.M.; Hombrebueno, J.R.; De Juan, J.
Identification and cellular location of glutamine synthetase in human sperm
Cell Tissue Res.
350
183-187
2012
Homo sapiens
Manually annotated by BRENDA team
Sohn, B.H.; Park, I.Y.; Shin, J.H.; Yim, S.Y.; Lee, J.S.
Glutamine synthetase mediates sorafenib sensitivity in beta-catenin-active hepatocellular carcinoma cells
Exp. Mol. Med.
50
e421
2018
Homo sapiens (P15104)
Manually annotated by BRENDA team
Tardito, S.; Oudin, A.; Ahmed, S.U.; Fack, F.; Keunen, O.; Zheng, L.; Miletic, H.; Sakariassen, P.?.; Weinstock, A.; Wagner, A.; Lindsay, S.L.; Hock, A.K.; Barnett, S.C.; Ruppin, E.; Morkve, S.H.; Lund-Johansen, M.; Chalmers, A.J.; Bjerkvig, R.; Niclou, S.P.; Gottlieb, E.
Glutamine synthetase activity fuels nucleotide biosynthesis and supports growth of glutamine-restricted glioblastoma
Nat. Cell Biol.
17
1556-1568
2015
Homo sapiens
Manually annotated by BRENDA team