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IUBMB CommentsThis enzyme participates in the eukaryotic ubiquitin-dependent Arg/N-end rule pathway of protein degradation, promoting the turnover of intracellular proteins that initiate with Met-Gln. Following the acetylation and removal of the initiator methionine, the exposed N-terminal glutamine is deaminated, resulting in its conversion to L-glutamate. The latter serves as a substrate for EC 2.3.2.8, arginyltransferase, making the protein susceptible to arginylation, polyubiquitination and degradation as specified by the N-end rule.
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N-terminal L-glutaminyl-[DHFRbt] + H2O
N-terminal L-glutamyl-[DHFRbt] + NH3
substrate is Escherichia coli dihydrofolate reductase (DHFR) moiety fused to a C-terminal peptide (denoted as bt) that is biotinylated in vivo
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N-terminal L-glutaminyl-[protein] + H2O
N-terminal L-glutamyl-[protein] + NH3
QKGSGAW + H2O
EKGSGAW + NH3
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QLGSGAW + H2O
ELGSGAW + NH3
about 80% of the activity compared to QKGSGAW
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additional information
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N-terminal L-glutaminyl-[protein] + H2O
N-terminal L-glutamyl-[protein] + NH3
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N-terminal L-glutaminyl-[protein] + H2O
N-terminal L-glutamyl-[protein] + NH3
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N-terminal L-glutaminyl-[protein] + H2O
N-terminal L-glutamyl-[protein] + NH3
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N-terminal L-glutaminyl-[protein] + H2O
N-terminal L-glutamyl-[protein] + NH3
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N-terminal L-glutaminyl-[protein] + H2O
N-terminal L-glutamyl-[protein] + NH3
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N-terminal L-glutaminyl-[protein] + H2O
N-terminal L-glutamyl-[protein] + NH3
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additional information
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the amidohydrolase activity of the native enzyme and of proteolytic fragments is analyzed using either L-glutamine or gamma-L-glutamic 4-nitroanilide as substrates
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additional information
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dual specificity of yeast Nta1 (yNta1), importance of second-position residues in Asn/Gln-bearing N-terminal degradation signals (N-degrons), also cf. EC 3.5.1.121. Specific hydrogen bonds stabilize interactions between N-degron peptides and hydrophobic peripheral regions of the active site pocket, interactions between Nta1 and N-degron peptides, detailed overview. The enzyme shows glutamine-specific enzyme activity with dipeptides Gln-Val and Gln-Gly, Michaelis-Menten kinetics
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additional information
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dual specificity of yeast Nta1 (yNta1), importance of second-position residues in Asn/Gln-bearing N-terminal degradation signals (N-degrons), also cf. EC 3.5.1.121. Specific hydrogen bonds stabilize interactions between N-degron peptides and hydrophobic peripheral regions of the active site pocket, interactions between Nta1 and N-degron peptides, detailed overview. The enzyme shows glutamine-specific enzyme activity with dipeptides Gln-Val and Gln-Gly, Michaelis-Menten kinetics
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N-terminal L-glutaminyl-[protein] + H2O
N-terminal L-glutamyl-[protein] + NH3
N-terminal L-glutaminyl-[protein] + H2O
N-terminal L-glutamyl-[protein] + NH3
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N-terminal L-glutaminyl-[protein] + H2O
N-terminal L-glutamyl-[protein] + NH3
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N-terminal L-glutaminyl-[protein] + H2O
N-terminal L-glutamyl-[protein] + NH3
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N-terminal L-glutaminyl-[protein] + H2O
N-terminal L-glutamyl-[protein] + NH3
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N-terminal L-glutaminyl-[protein] + H2O
N-terminal L-glutamyl-[protein] + NH3
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N-terminal L-glutaminyl-[protein] + H2O
N-terminal L-glutamyl-[protein] + NH3
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evolution
Ntaq1 and its crystal structure indicate that the active site and catalytic mechanism of NtQ-amidase are similar to those of transglutaminases
evolution
Ntaq1 and its crystal structure indicate that the active site and catalytic mechanism of NtQ-amidase are similar to those of transglutaminases
evolution
Ntaq1 and its crystal structure indicate that the active site and catalytic mechanism of NtQ-amidase are similar to those of transglutaminases
evolution
Ntaq1 and its crystal structure indicate that the active site and catalytic mechanism of NtQ-amidase are similar to those of transglutaminases
evolution
the catalytic triad, comprising Cys28, His81, and Asp97, is highly conserved among Ntaq proteins, transglutaminases, and cysteine proteases of diverse organisms
malfunction
a mutant in the Drosophila Cg8253 gene, encoding NtQ-amidase, has defective long-term memory
malfunction
downregulation of Ntaq1 in mouse cells results in a decrease of NtQ-amidase activity
metabolism
the enzyme is involved in the the N-end rule pathway, overview
metabolism
the enzyme is involved in the the N-end rule pathway, overview
metabolism
the enzyme is involved in the the N-end rule pathway, overview
metabolism
the enzyme is involved in the the N-end rule pathway, overview
metabolism
the first step of the hierarchically organized Arg/N-end rule pathway of protein degradation is deamidation of the N-terminal glutamine and asparagine residues of substrate proteins to glutamate and aspartate, respectively. These reactions are catalyzed by the N-terminal amidase (Nt-amidase) Nta1 in fungi such as Saccharomyces cerevisiae, and by the glutamine-specific Ntaq1 and asparagine-specific Ntan1 Nt-amidases in mammals. Specific deamidation mechanisms in the first step of the N-end rule pathway, overview
physiological function
enzyme Ntaq is an initial component of the N-end rule pathway and converts N-terminal glutamine to glutamate
physiological function
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the proteolysis of native glucosamine-6-phosphate synthase of molecular weight67 kDa from Escherichia coli using cr-chymotrypsin generates two nonoverlapping polypeptides CT1 and CT2 of molecular weight40 kDa and 27 kDa lacking glucosamine-6-phosphate synthesizing activity. N-terminal and C-terminal sequence analyses shows that cleavage occurs between positions 240 and 241 of the primary sequence without further degradation. The glutamine amidohydrolase activity is located in the CT2 N-terminal polypeptide which is capable of incorporating glutamine site-directed affinity label [2-3H]-iV3-(4-methoxyfumaroyl)-diaminopropionic acid, it bears the amidotransferase function. CT1 displays a higher reactivity than CT2 for fructose 6-phosphate binding contains the ketose/aldose isomerase activity
physiological function
the enzyme controls the expression of specific defence-response genes, activates the synthesis pathway for the phytoalexin camalexin and influences basal resistance to the hemibiotroph pathogen Pseudomonas syringae pv tomato
additional information
substrate binding structure, molecular docking studies of tripeptides with N-terminal glutamine, overview. Upon binding of a substrate with N-terminal glutamine, active site catalytic triad mediates the deamination of the N-terminal residue to glutamate by a mechanism analogous to that of cysteine proteases. Active site structure, ooverview
additional information
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substrate binding structure, molecular docking studies of tripeptides with N-terminal glutamine, overview. Upon binding of a substrate with N-terminal glutamine, active site catalytic triad mediates the deamination of the N-terminal residue to glutamate by a mechanism analogous to that of cysteine proteases. Active site structure, ooverview
additional information
three-dimensional structure, mutational analysis, and mechanism of Ntaq1 NtQ-amidase, comparisons of mouse, human, and bovine enzymes, overview
additional information
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three-dimensional structure, mutational analysis, and mechanism of Ntaq1 NtQ-amidase, comparisons of mouse, human, and bovine enzymes, overview
additional information
three-dimensional structure, mutational analysis, and mechanism of Ntaq1 NtQ-amidase, comparisons of mouse, human, and bovine enzymes, overview
additional information
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three-dimensional structure, mutational analysis, and mechanism of Ntaq1 NtQ-amidase, comparisons of mouse, human, and bovine enzymes, overview
additional information
three-dimensional structure, mutational analysis, and mechanism of Ntaq1 NtQ-amidase, comparisons of mouse, human, and bovine enzymes, overview
additional information
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three-dimensional structure, mutational analysis, and mechanism of Ntaq1 NtQ-amidase, comparisons of mouse, human, and bovine enzymes, overview
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monomer
in solution, yNta1 is a monomer containing 14 beta-strands, 11 alpha-helices, and three 310-helices. The core region of the enzyme shows antiparallel and parallel mixed beta-sheets surrounded by helices, and these sixstranded beta-sheets face each other
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x * 26000, native enzyme, SDS-PAGE
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x * 40000, CT1 polypeptide fragment of glucosamine-6-phosphate synthase, SDS-PAGE
additional information
the enzyme structure reveals a monomeric globular protein with alpha-beta-alpha three-layer sandwich architecture. The catalytic triad located in the active site, Cys-His-Asp, is highly conserved among Ntaq family and transglutaminases from diverse organisms. Substrate binding mode of hNtaq1 with the N-terminus of a symmetry-related Ntaq1 molecule bound in the substrate binding cleft
additional information
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the enzyme structure reveals a monomeric globular protein with alpha-beta-alpha three-layer sandwich architecture. The catalytic triad located in the active site, Cys-His-Asp, is highly conserved among Ntaq family and transglutaminases from diverse organisms. Substrate binding mode of hNtaq1 with the N-terminus of a symmetry-related Ntaq1 molecule bound in the substrate binding cleft
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crystal structure analysis of C8orf32/Ntaq1
purified enzyme Ntaq1 bound with the N-terminus of a symmetry-related Ntaq1 molecule, hanging drop vapor diffusion method, mixing of 10 mg/ml protein in 50 mM sodium chloride, 3 mM sodium azide, 0.3 mM TCEP, and 100 mM Bis-Tris, pH 7.0, with well solution containing 1% ethylene glycol, 1.8 M ammonium sulfate, 100 mM MES, pH 6.0, in 1:1 ratio, at 18°C, X-ray diffraction structure determination and analysis at 1.5 A resolution
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Denisot, M.; Goffic, F.; Badet, B.
Glucosamine-6-phosphate synthase from Escherichia coli yields two proteins upon limited proteolysis: identification of the glutamine amidohydrolase and 2R ketose/aldose isomerase-bearing domains based on their biochemical properties
Arch. Biochem. Biophys.
288
225-230
1991
Escherichia coli
brenda
Wang, H.; Piatkov, K.I.; Brower, C.S.; Varshavsky, A.
Glutamine-specific N-terminal amidase, a component of the N-end rule pathway
Mol. Cell
34
686-695
2009
Bos taurus (Q3T0D3), Bos taurus, Drosophila melanogaster (Q7K2Y9), Mus musculus (Q80WB5), Mus musculus, Homo sapiens (Q96HA8), Homo sapiens
brenda
Park, M.S.; Bitto, E.; Kim, K.R.; Bingman, C.A.; Miller, M.D.; Kim, H.J.; Han, B.W.; Phillips, G.N.
Crystal structure of human protein N-terminal glutamine amidohydrolase, an initial component of the N-end rule pathway
PLoS ONE
9
e111142
2014
Homo sapiens (Q96HA8), Homo sapiens
brenda
Kim, M.K.; Oh, S.J.; Lee, B.G.; Song, H.K.
Structural basis for dual specificity of yeast N-terminal amidase in the N-end rule pathway
Proc. Natl. Acad. Sci. USA
113
12438-12443
2016
Saccharomyces cerevisiae (P40354), Saccharomyces cerevisiae
brenda
Vicente, J.; Mendiondo, G.M.; Pauwels, J.; Pastor, V.; Izquierdo, Y.; Naumann, C.; Movahedi, M.; Rooney, D.; Gibbs, D.J.; Smart, K.; Bachmair, A.; Gray, J.E.; Dissmeyer, N.; Castresana, C.; Ray, R.V.; Gevaert, K.; Holdsworth, M.J.
Distinct branches of the N-end rule pathway modulate the plant immune response
New Phytol.
221
988-1000
2019
Arabidopsis thaliana (O22944), Arabidopsis thaliana
brenda
3.5.1.122 protein N-terminal glutamine amidohydrolase
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