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Information on EC 2.3.1.1 - amino-acid N-acetyltransferase and Organism(s) Homo sapiens and UniProt Accession Q8N159
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2.3.1.1 amino-acid N-acetyltransferaseIUBMB Comments
Also acts with L-aspartate and, more slowly, with some other amino acids.
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Word Map
- 2.3.1.1
- ammonia
-
hyperammonemia
- ornithine
- l-arginine
- citrulline
- carbamylphosphate
-
ureagenesis
-
transcarbamylase
-
carglumic
- accoa
-
6.3.4.16
-
gcn5-related
-
protein-restricted
- carbamylglutamate
-
nagks
-
feedback-resistant
- phenylbutyrate
-
ureotelic
- analysis
- medicine
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
Synonyms
n-acetylglutamate synthase, n-acetylglutamate synthetase, acetylglutamate synthase, n-acetyl-l-glutamate synthase, nags-k, acetylglutamate synthetase, nags/k, rv2747, n-acetyl-l-glutamate synthetase, n-acetylglutamate synthase/kinase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
acetylglutamate synthase
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-
-
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acetylglutamate synthetase
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-
-
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acetylglutamic synthetase
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-
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acetyltransferase, amino acid
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AGAS
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-
-
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amino acid acetyltransferase
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-
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N-acetyl-L-glutamate synthetase
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-
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N-acetylglutamate synthase
N-acetylglutamate synthetase
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-
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N-acetylglutamate synthase
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-
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
acetyl-CoA + L-glutamate = CoA + N-acetyl-L-glutamate
rapid-equilibrium random bi bi mechanism
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Acyl group transfer
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-
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PATHWAY SOURCE
PATHWAYS
BRENDA
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-, -, -
SYSTEMATIC NAME
IUBMB Comments
acetyl-CoA:L-glutamate N-acetyltransferase
Also acts with L-aspartate and, more slowly, with some other amino acids.
CAS REGISTRY NUMBER
COMMENTARY
9029-88-3
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
butyryl-CoA + L-glutamate
CoA + N-butyryl-L-glutamate
-
low activity compared to acetyl-CoA
-
-
?
propionyl-CoA + L-glutamate
CoA + N-propionyl-L-glutamate
-
low activity compared to acetyl-CoA
-
-
?
acetyl-CoA + L-glutamate
CoA + N-acetyl-L-glutamate
-
CoA and N-acetyl-L-glutamate binding sites structure analysis from crystal structure, detailed overview
-
?
acetyl-CoA + L-glutamate
CoA + N-acetyl-L-glutamate
-
-
-
-
?
acetyl-CoA + L-glutamate
CoA + N-acetyl-L-glutamate
-
the product N-acetyl-L-glutamate serves as an allosteric activator of carbamoylphosphate synthetase 1, the first enzyme of the urea cycle. Autosomal recessive inherited NAGS deficiency leads to severe neonatal or late-onset hyperammonemia
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-
?
additional information
?
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-
the N-acetyl-L-glutamate synthase contains an N-terminal catalytic N-acetyltransferase domain and a C-terminal amino acid kinase domain
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-
?
additional information
?
-
the N-acetyl-L-glutamate synthase contains an N-terminal catalytic N-acetyltransferase domain and a C-terminal amino acid kinase domain
-
-
?
additional information
?
-
-
autosomal recessively inherited enzyme deficiency causes severe neonatal or late-onset hyperammonemia, the enzyme is an allosteric activator of the carbamoylphosphate synthase I, the first enzyme of the urea cycle
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-
?
additional information
?
-
-
enzyme deficiency causes hyperammonemia, presumably due to loss of carbamoylphosphate synthase I activity
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-
?
additional information
?
-
-
no activity with isobutyryl-CoA, isovaleryl-CoA, 3-methylcrotonyl-CoA, methylmalonyl-CoA, succinyl-CoA, and glutaryl-CoA
-
-
?
additional information
?
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-
the enzyme has little activity with glutamine (5.0%) and glycine (2.9%) and no acetylation of other amino acids (less than 1.0%) as well as low activity with propionyl-CoA (4.3%) and no activity with other acyl-CoA derivatives
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
acetyl-CoA + L-glutamate
CoA + N-acetyl-L-glutamate
-
-
-
-
?
acetyl-CoA + L-glutamate
CoA + N-acetyl-L-glutamate
-
the product N-acetyl-L-glutamate serves as an allosteric activator of carbamoylphosphate synthetase 1, the first enzyme of the urea cycle. Autosomal recessive inherited NAGS deficiency leads to severe neonatal or late-onset hyperammonemia
-
-
?
additional information
?
-
-
the N-acetyl-L-glutamate synthase contains an N-terminal catalytic N-acetyltransferase domain and a C-terminal amino acid kinase domain
-
-
?
additional information
?
-
the N-acetyl-L-glutamate synthase contains an N-terminal catalytic N-acetyltransferase domain and a C-terminal amino acid kinase domain
-
-
?
additional information
?
-
-
autosomal recessively inherited enzyme deficiency causes severe neonatal or late-onset hyperammonemia, the enzyme is an allosteric activator of the carbamoylphosphate synthase I, the first enzyme of the urea cycle
-
-
?
additional information
?
-
-
enzyme deficiency causes hyperammonemia, presumably due to loss of carbamoylphosphate synthase I activity
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
L-arginine
allosteric activator, the binding site of the activator is located in the amino acid kinase domain of the enzyme
additional information
-
dilution of the purified recombinant enzyme results in an increase in activity
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.94
acetyl-CoA
mature enzyme without affinity tag, in presence of 1 mM Arg
2.5
L-glutamate
mature enzyme without affinity tag, in presence of 1 mM Arg
additional information
additional information
Michaelis-Menten kinetics
-
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
0.139
-
purified recombinant His-tagged enzyme in 10fold dilution, in absence of L-arginine
0.163
-
purified recombinant His-tagged enzyme in 10fold dilution, in presence of L-arginine
0.325
-
purified recombinant His-tagged enzyme in 50fold dilution, in absence of L-arginine
0.359
-
purified recombinant His-tagged enzyme in 50fold dilution, in presence of L-arginine
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
8.5
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
the enzyme contains an N-terminal putative mitochondrial targeting sequence
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
enzyme deficiency results in elevated levels of plasma ammonia which is neurotoxic
physiological function
N-acetylglutamate synthase catalyzes the synthesis of N-acetyl-L-glutamate, an obligate cofactor for carbamyl phosphate synthetase I in the urea cycle. An N-terminal proline-rich motif of the enzyme is likely to function in signal transduction to carbamyl phosphate synthetase I, CPS1
malfunction
enzyme deficiency results in elevated levels of plasma ammonia which is neurotoxic
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). NAGS_HUMAN
534
0
58156
Swiss-Prot
Mitochondrion (Reliability: 3)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
proteolytic modification
-
2 processed forms with different N-terminal truncations are produced, i.e. a long and a short mature form
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
purified recombinant catalytic N-acetyltransferase domain complexed with N-acetyl-L-glutamate, sitting drop vapour diffusion method, mixing of 0.002 ml of 20 mg/ml protein in 50 mM Tris-HCl, pH 7.4, 50 mM NaCl, 10% glycerol, 5 mM bmercaptoethanol, and 1 mM EDTA, 10 m CoA, and 10 mM N-acetyl-L-glutamate, with 0.002 ml of reservoir solution containing 100 mM Bis-Tris, pH 6.5, 35% PEG 3350, 18°C, X-ray diffraction structure determination and analysis at 2.1 A resolution, molecular replacement
catalytic N-acetyltransferase domain complexed with N-acetyl-L-glutamate, hanging drop vapor diffusion method, using 100 mM Bis-Tris, pH 6.5, 35% (w/v) PEG3350
development of a structural model of human enzyme that is fully consistent with the functional effects of the 14 missense mutations that have been identified in N-acetylglutamate synthase-deficient patients
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
N479A
site-directed mutagenesis, an active site mutant with reduced activity compared to the wild-type enzyme
Y441F
site-directed mutagenesis, an active site mutant with reduced activity compared to the wild-type enzyme
Y485F
site-directed mutagenesis, an active site mutant with reduced activity compared to the wild-type enzyme
A518T
C200R
L430P
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naturally occurring mutation of a turkish patient suffering hyperammonemia, reconstruction of the mutation by site-directed mutagenesis, mutant enzyme shows reduced activity compared to the wild-type enzyme
S410P
W484R
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naturally occurring mutation of a turkish patient suffering hyperammonemia, reconstruction of the mutation by site-directed mutagenesis, mutant enzyme reduced activity compared to the wild-type enzyme
additional information
A518T
-
naturally occurring mutation of a turkish patient suffering hyperammonemia, reconstruction of the mutation by site-directed mutagenesis, mutant enzyme shows over 95% reduced activity compared to the wild-type enzyme
A518T
-
mutant enzymes from patients with NAGS missense mutations are overexpressed in Escherichia coli NK5992. All mutated proteins show severe decrease in enzyme activity providing evidence for the disease-causing nature of the mutations
C200R
-
naturally occurring mutation of a french patient suffering hyperammonemia, reconstruction of the mutation by site-directed mutagenesis, mutant enzyme shows over 95% reduced activity compared to the wild-type enzyme
C200R
-
mutant enzymes from patients with NAGS missense mutations are overexpressed in Escherichia coli NK5992. All mutated proteins show severe decrease in enzyme activity providing evidence for the disease-causing nature of the mutations
S410P
-
naturally occurring mutation of an algerian patient suffering hyperammonemia, reconstruction of the mutation by site-directed mutagenesis, mutant enzyme shows over 95% reduced activity compared to the wild-type enzyme
S410P
-
mutant enzymes from patients with NAGS missense mutations are overexpressed in Escherichia coli NK5992. All mutated proteins show severe decrease in enzyme activity providing evidence for the disease-causing nature of the mutations
additional information
report of 21 mutations that cause NAGS deficiency. A total of 10 disease-causing mutations are associated with acute neonatal hyperammonemia. The remaining mutations are found in patients with late onset disease. Residual enzymatic activities are included in this report and the deleterious effects of eight mutations are confirmed by expression studies
additional information
-
report of 21 mutations that cause NAGS deficiency. A total of 10 disease-causing mutations are associated with acute neonatal hyperammonemia. The remaining mutations are found in patients with late onset disease. Residual enzymatic activities are included in this report and the deleterious effects of eight mutations are confirmed by expression studies
additional information
-
the isolated catalytic N-acetyltransferase domain retains catalytic activity in the absence of the amino acid kinase domain
additional information
the isolated catalytic N-acetyltransferase domain retains catalytic activity in the absence of the amino acid kinase domain
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
use of silicone-treated glassware or plastic tubes, e.g. polyethylene, polycarbonate or polypropylene stabilizes the enzyme
-
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant His-tagged wild-type and mutant enzymes from Escherichia coli strain BL21(DE3) by nickel affinity chromatography and cation exchange chromatography, the His-tag is ceaved by thrombin
recombinant His-tagged enzyme from Escherichia coli strain BL21(DE3) by nickel affinity chromatography
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant expression of His-tagged wild-type and mutant enzymes, and isolated catalytic N-acetyltransferase domain in Escherichia coli strain BL21(DE3)
gene structure, His-tagged wild-type and mutant enzymes in enzyme-deficient Escherichia coli strain NK 5992
-
mutent enzymes from patients with NAGS missense mutations are overexpressed in Escherichia coli NK5992. All mutated proteins show severe decrease in enzyme activity providing evidence for the disease-causing nature of the mutations
-
overexpression of His-tagged enzyme in Escherichia coli strain BL21(DE3), functional complementation of an enzyme-deficient Escherichia coli strain argA-
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
analysis
assay using UPLC-MS/MS in conjunction with stable isotope (N-acetylglutamic-2,3,3,4,4-d5 acid) dilution for the quantitative detection of N-acetylglutamate produced by NAGS
medicine
warly, accurate, and specific diagnosis of NAGS deficiency is critical since this condition can be successfully treated with N-carbamoylglutamate. Treatment with N-carbamoylglutamate should be initiated as soon as a patient is suspected of having NAGS deficiency. Molecular testing represents the most reliable method of diagnosis
medicine
-
a polar body-based preimplantation genetic diagnosis for N -acetylglutamate synthase deficiency using multiplex and fluorescent single-cell PCR is described
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Powers-Lee, S.G.
N-Acetylglutamate synthase
Methods Enzymol.
113
27-35
1985
Escherichia coli, Homo sapiens, Pseudomonas aeruginosa, Rattus norvegicus, Salmonella enterica subsp. enterica serovar Typhimurium
Wakabayashi, Y.; Iwashima, A.; Yamada, E.; Yamada, R.
Enzymological evidence for the indispensability of small intestine in the synthesis of arginine from glutamate. II. N-acetylglutamate synthase
Arch. Biochem. Biophys.
291
9-14
1991
Homo sapiens, Rattus norvegicus
Bachmann, C.; Krahenbuhl, S.; Colombo, J.P.
Purification and properties of acetyl-CoA:L-glutamate N-acetyltransferase from human liver
Biochem. J.
205
123-127
1982
Homo sapiens
Schmidt, E.; Nuoffer, J.M.; Haberle, J.; Pauli, S.; Guffon, N.; Vianey-Saban, C.; Wermuth, B.; Koch, H.G.
Identification of novel mutations of the human N-acetylglutamate synthase gene and their functional investigation by expression studies
Biochim. Biophys. Acta
1740
54-59
2005
Homo sapiens
Morizono, H.; Caldovic, L.; Shi, D.; Tuchman, M.
Mammalian N-acetylglutamate synthase
Mol. Genet. Metab.
81 Suppl 1
S4-11
2004
Homo sapiens, Mus musculus
Caldovic, L.; Morizono, H.; Tuchman, M.
Mutations and polymorphisms in the human N-acetylglutamate synthase (NAGS) Gene
Hum. Mutat.
28
754-759
2007
Homo sapiens (Q8N159), Homo sapiens
Caldovic, L.; Lopez, G.Y.; Haskins, N.; Panglao, M.; Shi, D.; Morizono, H.; Tuchman, M.
Biochemical properties of recombinant human and mouse N-acetylglutamate synthase
Mol. Genet. Metab.
87
226-232
2006
Homo sapiens (Q8N159), Homo sapiens, Mus musculus (Q8R4H7), Mus musculus
Altarescu, G.; Brooks, B.; Eldar-Geva, T.; Margalioth, E.J.; Singer, A.; Levy-Lahad, E.; Renbaum, P.
Polar Body-Based Preimplantation Genetic Diagnosis for N-Acetylglutamate Synthase Deficiency
Fetal. Diagn. Ther.
24
170-176
2008
Homo sapiens
Shi, D.; Li, Y.; Cabrera-Luque, J.; Jin, Z.; Yu, X.; Zhao, G.; Haskins, N.; Allewell, N.M.; Tuchman, M.
A novel N-acetylglutamate synthase architecture revealed by the crystal structure of the bifunctional enzyme from Maricaulis maris
PLoS ONE
6
e28825
2011
Homo sapiens, Maricaulis maris (Q0ASS9), Maricaulis maris
Dercksen, M.; IJlst, L.; Duran, M.; Mienie, L.J.; van Cruchten, A.; van der Westhuizen, F.H.; Wanders, R.J.
Inhibition of N-acetylglutamate synthase by various monocarboxylic and dicarboxylic short-chain coenzyme A esters and the production of alternative glutamate esters
Biochim. Biophys. Acta
1842
2510-2516
2014
Homo sapiens
Shi, D.; Allewell, N.M.; Tuchman, M.
The N-acetylglutamate synthase family: structures, function and mechanisms
Int. J. Mol. Sci.
16
13004-13022
2015
Escherichia coli, Homo sapiens, Rattus norvegicus
Zhao, G.; Jin, Z.; Allewell, N.M.; Tuchman, M.; Shi, D.
Crystal structure of the N-acetyltransferase domain of human N-acetyl-L-glutamate synthase in complex with N-acetyl-L-glutamate provides insights into its catalytic and regulatory mechanisms
PLoS ONE
8
e70369
2013
Homo sapiens, Homo sapiens (Q8N159)
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