Information on EC 1.14.11.16 - peptide-aspartate beta-dioxygenase

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The expected taxonomic range for this enzyme is: Eutheria

EC NUMBER
COMMENTARY
1.14.11.16
-
RECOMMENDED NAME
GeneOntology No.
peptide-aspartate beta-dioxygenase
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
peptide-L-aspartate + 2-oxoglutarate + O2 = peptide-3-hydroxy-L-aspartate + succinate + CO2
show the reaction diagram
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
decarboxylation
-
-
hydroxylation
-
-
-
-
hydroxylation
-
-
oxidation
-
-
-
-
redox reaction
-
-
-
-
reduction
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
peptide-L-aspartate,2-oxoglutarate:oxygen oxidoreductase (3-hydroxylating)
Requires Fe2+. Some vitamin K-dependent coagulation factors, as well as synthetic peptides based on the structure of the first epidermal growth factor domain of human coagulation factor IX or X, can act as acceptors.
SYNONYMS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
aspartate beta-hydroxylase
-
-
-
-
aspartyl (asparaginyl) beta-hydroxylase
-
-
aspartyl (asparaginyl)-beta-hydroxylase
-
-
aspartyl beta-hydroxylase
-
-
aspartyl-(asparaginyl) beta-hydroxylase
-
-
aspartyl-(asparaginyl)-b-hydroxylase
-
-
aspartyl-(asparaginyl)-beta-hydroxylase
-
-
aspartyl-(asparagyl)-beta-hydroxylase
-
-
aspartyl-asparaginyl-beta-hydroxylase
-
-
aspartylpeptide beta-dioxygenase
-
-
-
-
EGF beta-hydroxylase
-
-
EGFH
-
-
factor inhibiting HIF
-
-
factor inhibiting hypoxia-inducible factor
-
-
factor inhibiting hypoxia-inducible transcription factor (HIF)
-
-
factor-inhibiting hypoxia-inducible factor
-
-
HIF asparaginyl hydroxylase
-
-
human aspartyl (asparaginyl) beta-hydroxylase
-
-
hypoxia-inducible factor asparaginyl hydroxylase
-
-
CAS REGISTRY NUMBER
COMMENTARY
122544-66-5
-
ORGANISM
COMMENTARY
LITERATURE
SEQUENCE CODE
SEQUENCE DB
SOURCE
human osteosarcoma
-
-
Manually annotated by BRENDA team
three different size transcripts 2.8, 4.5 and 6.6 kb, the bigger ones lead to active proteins after expression
-
-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
malfunction
-
inhibition by fetal alcohol spectrum disorder, decrease leads to impairment in neuronal migration
physiological function
-
mediates neuronal motility
physiological function
-
stimulates cell migration
SUBSTRATE
PRODUCT                      
REACTION DIAGRAM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
ankyrin repeat domain of endogenous Notch receptor L-asparagine + 2-oxoglutarate + O2
ankyrin repeat domain of endogenous Notch receptor 3-hydroxy-L-asparagine + succinate + CO2
show the reaction diagram
-
hydroxylation of highly conserved asparaginyl residues within the ankyrin repeat
-
-
?
ankyrin repeat domain of endogenous Notch receptor L-asparagine + 2-oxoglutarate + O2
ankyrin repeat domain of endogenous Notch receptor 3-hydroxy-L-asparagine + succinate + CO2
show the reaction diagram
-
hydroxylation of hyghly conserved asparaginyl residues within the ankyrin repeat
-
-
?
ankyrin repeat domain protein
?
show the reaction diagram
-
a maximum of three ankyrin repeats enables ankyrin repeat domain proteins as a substrate
-
-
?
HIF (L-Asn803) + 2-oxoglutarate + O2
HIF (3-hydroxy-L-Asn803) + succinate + CO2
show the reaction diagram
-
accepts HIF-1alpha and HIF-2-alpha as substrate, HIF mutant V802A exhibits 4fold lower substrate activity than native protein, no activity with N803A mutant
-
-
?
peptide L-asparagine + 2-oxoglutarate + O2
peptide 3-hydroxy-L-asparagine + succinate + CO2
show the reaction diagram
-
-
-
-
?
peptide L-asparagine + 2-oxoglutarate + O2
peptide 3-hydroxy-L-asparagine + succinate + CO2
show the reaction diagram
Q9NWT6
-
-
-
?
peptide L-asparagine + 2-oxoglutarate + O2
peptide 3-hydroxy-L-asparagine + succinate + CO2
show the reaction diagram
-
-
-
-
?
peptide L-asparagine + 2-oxoglutarate + O2
peptide 3-hydroxy-L-asparagine + succinate + CO2
show the reaction diagram
-
-
-
-
?
peptide L-asparagine + 2-oxoglutarate + O2
peptide 3-hydroxy-L-asparagine + succinate + CO2
show the reaction diagram
-
first epidermal growth factor-like domain of bovine protein S with an asparagine replacing the aspartic acid at position 18
-
-
?
peptide L-asparagine + 2-oxoglutarate + O2
peptide 3-hydroxy-L-asparagine + succinate + CO2
show the reaction diagram
-
first epidermal growth factor-like domain of human protein S with an asparagine replacing the aspartic acid at position 18
-
-
?
peptide L-asparagine + 2-oxoglutarate + O2
peptide 3-hydroxy-L-asparagine + succinate + CO2
show the reaction diagram
-
enzyme catalyzes the erythro-beta-hydroxylation of asparaginyl and aspartyl residues to form the 2S, 3R-product, possible role in the Notch signalling pathway, hydroxylation of Asn803 in hypoxia-inducible transcription factor, converted protein is incapable in interacting with the transcripitonal coactivator p300
-
-
?
peptide L-asparagine + 2-oxoglutarate + O2
peptide 3-hydroxy-L-asparagine + succinate + CO2
show the reaction diagram
-
hydroxylation of Asn803 in hypoxia-inducible transcription factor, converted protein is incapable in interacting with the transcripitonal coactivator p300
-
-
?
peptide L-asparagine + 2-oxoglutarate + O2
peptide 3-hydroxy-L-asparagine + succinate + CO2
show the reaction diagram
Q9NWT6
hydroxylation of Asn803 in hypoxia-inducible transcription factor, converted protein is incapable in interacting with the transcripitonal coactivator p300
-
-
?
peptide L-aspartate + 2-oxoglutarate + O2
peptide 3-hydroxy-L-aspartate + succinate + CO2
show the reaction diagram
-
-
-
?
peptide L-aspartate + 2-oxoglutarate + O2
peptide 3-hydroxy-L-aspartate + succinate + CO2
show the reaction diagram
-
-
-
?
peptide L-aspartate + 2-oxoglutarate + O2
peptide 3-hydroxy-L-aspartate + succinate + CO2
show the reaction diagram
-
first epidermal growth factor-like domain of bovine protein S as substrate
-
?
peptide L-aspartate + 2-oxoglutarate + O2
peptide 3-hydroxy-L-aspartate + succinate + CO2
show the reaction diagram
-
first epidermal growth factor-like domain of human protein S as substrate
-
?
peptide L-aspartate + 2-oxoglutarate + O2
peptide 3-hydroxy-L-aspartate + succinate + CO2
show the reaction diagram
-
first epidermal growth factor-like domain of human protein S as substrate
-
?
peptide L-aspartate + 2-oxoglutarate + O2
peptide 3-hydroxy-L-aspartate + succinate + CO2
show the reaction diagram
-
specific erythro-hydroxylation
-
?
peptide L-aspartate + 2-oxoglutarate + O2
peptide 3-hydroxy-L-aspartate + succinate + CO2
show the reaction diagram
-
specific erythro-hydroxylation
-
?
peptide L-aspartate + 2-oxoglutarate + O2
peptide 3-hydroxy-L-aspartate + succinate + CO2
show the reaction diagram
-
first epidermal growth factor-like domain of human factor IX as substrate
-
?
peptide L-aspartate + 2-oxoglutarate + O2
peptide 3-hydroxy-L-aspartate + succinate + CO2
show the reaction diagram
-
second epidermal growth factor-like domain of bovine protein S
-
?
peptide L-aspartate + 2-oxoglutarate + O2
peptide 3-hydroxy-L-aspartate + succinate + CO2
show the reaction diagram
-
hydroxylates epidermal growth factor-like domains in transformation-associated proteins
-
?
HIF-1alpha peptide Asp788-Leu822 (L-Asn803) + 2-oxoglutarate + O2
HIF-1alpha peptide Asp788-Leu822 (3-hydroxy-L-Asn803) + succinate + CO2
show the reaction diagram
Q9NWT6
much lower activity with peptides lacking residues 819-822, 807-822, and 815-822
-
-
?
additional information
?
-
-
overexpression may be associated with malignant transformation
-
-
-
additional information
?
-
-
overexpression may be associated with malignant transformation
-
-
-
additional information
?
-
-
the enzyme hydroxylates epidermal growth factor-like domains in transformation-associated proteins
-
-
-
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
peptide L-asparagine + 2-oxoglutarate + O2
peptide 3-hydroxy-L-asparagine + succinate + CO2
show the reaction diagram
-
enzyme catalyzes the erythro-beta-hydroxylation of asparaginyl and aspartyl residues to form the 2S, 3R-product, possible role in the Notch signalling pathway, hydroxylation of Asn803 in hypoxia-inducible transcription factor, converted protein is incapable in interacting with the transcripitonal coactivator p300
-
-
?
peptide L-asparagine + 2-oxoglutarate + O2
peptide 3-hydroxy-L-asparagine + succinate + CO2
show the reaction diagram
-
hydroxylation of Asn803 in hypoxia-inducible transcription factor, converted protein is incapable in interacting with the transcripitonal coactivator p300
-
-
?
peptide L-asparagine + 2-oxoglutarate + O2
peptide 3-hydroxy-L-asparagine + succinate + CO2
show the reaction diagram
Q9NWT6
hydroxylation of Asn803 in hypoxia-inducible transcription factor, converted protein is incapable in interacting with the transcripitonal coactivator p300
-
-
?
peptide L-aspartate + 2-oxoglutarate + O2
peptide 3-hydroxy-L-aspartate + succinate + CO2
show the reaction diagram
-
-
-
?
peptide L-aspartate + 2-oxoglutarate + O2
peptide 3-hydroxy-L-aspartate + succinate + CO2
show the reaction diagram
-
hydroxylates epidermal growth factor-like domains in transformation-associated proteins
-
?
additional information
?
-
-
overexpression may be associated with malignant transformation
-
-
-
additional information
?
-
-
overexpression may be associated with malignant transformation
-
-
-
additional information
?
-
-
the enzyme hydroxylates epidermal growth factor-like domains in transformation-associated proteins
-
-
-
METALS and IONS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
Fe2+
-
0.05 mM increases activity 6-fold
INHIBITORS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
2,2'-dipyridyl
-
at 1 mM 90% inhibition
ankyrin repeat domain
-
may function as a natural inhibitor and provide an oxygen-dependent interface that modulates hypoxia-induced factor signaling
-
dimethyloxalylglycine
-
-
Insulin-like growth factor-1
-
stimulates peptide-aspartate beta-dioxygenase protein expression and directional motility. Ethanol reduces the stimulation without inhibition of the mRNA expression
-
iodoacetamide
-
at 1 mM less than 5% activity, 2-oxoglutarate and EDTA protects
additional information
Q9NWT6
several 2-oxoglutarate analogs inhibits enzyme activity
-
additional information
-
phosphorylation by GSK-3beta oder degradation by caspase
-
additional information
-
development of a ScFv anti-HAAH antibody for specific in vivo inhibition of the enzyme by expression of His-tagged light and heavy chain cloned from the hybridoma cells G3/F11 in Escherichia coli strain BL21(DE3)PlysS/pET-16b, partly in inclusion bodies, or of c-myc-tagged ScFv in Escherichia coli strain HB2151/pHEN1, partly cytosolic. Variable regions of the genes of the heavy chain and light chain are connected with a flexible linker using an overlap extension PCR. Nucleotide sequence analysis revealed that the anti-HAAH VH was a member of the VH V gene family and the VL gene belonged to the Vk gene family VI subgroup
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
ascorbate
Q9NWT6
required
additional information
-
regulated by insulin and insulin-like growth factor
-
KM VALUE [mM]
KM VALUE [mM] Maximum
SUBSTRATE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.005
-
2-oxoglutarate
-
-
0.021
-
2-oxoglutarate
-
56 kDa protein
0.022
-
2-oxoglutarate
-
52 kDa protein
0.025
-
2-oxoglutarate
Q9NWT6
pH 7.8, 30C
0.098
-
2-oxoglutarate
-
at 1 mM Fe2+, H675D mutant
0.102
-
2-oxoglutarate
-
at 1 mM Fe2+, wild-type
0.125
-
2-oxoglutarate
-
at 1 mM Fe2+, H675E mutant
0.003
-
Fe2+
-
-
-
0.0083
-
Fe2+
-
56 kDa protein
-
0.0096
-
Fe2+
-
52 kDa protein
-
0.013
-
Fe2+
-
at 0.6 mM 2-oxoglutarate, wild-type
-
0.052
-
Fe2+
-
at 0.6 mM 2-oxoglutarate, H675E mutant
-
0.093
-
Fe2+
-
at 0.6 mM 2-oxoglutarate, H675D mutant
-
0.019
-
first epidermal growth factor-like domain
-
substrate is of human protein S with an asparagine replacing the aspartic acid at position 18, native enzyme
-
0.024
-
first epidermal growth factor-like domain
-
substrate is of human protein S with an asparagine replacing the aspartic acid at position 18, recombinant enzyme
-
0.034
-
first epidermal growth factor-like domain
-
substrate is of human protein S with an asparagine replacing the aspartic acid at position 18, 52 kDa protein
-
0.035
-
first epidermal growth factor-like domain
-
substrate is of human protein S with an asparagine replacing the aspartic acid at position 18, 56 kDa protein
-
0.067
-
first epidermal growth factor-like domain
-
substrate is of human protein S, 52 kDa protein
-
0.075
-
first epidermal growth factor-like domain
-
substrate is of human protein S, 56 kDa protein
-
0.1
-
HIF-1alpha peptide Asp788-Leu822 (L-asparagine803)
Q9NWT6
pH 7.8, 30C
-
0.09
-
O2
Q9NWT6
pH 7.8, 30C
TURNOVER NUMBER [1/s]
TURNOVER NUMBER MAXIMUM[1/s]
SUBSTRATE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.0167
-
first epidermal growth factor-like domain
-
substrate is of human protein S, 56 kDa protein
-
0.0217
-
first epidermal growth factor-like domain
-
substrate is of human protein S with an asparagine replacing the aspartic acid at position 18, 56 kDa protein
-
0.025
-
first epidermal growth factor-like domain
-
substrate is of human protein S, 52 kDa protein
-
0.0317
-
first epidermal growth factor-like domain
-
substrate is of human protein S with an asparagine replacing the aspartic acid at position 18, 52 kDa protein
-
SPECIFIC ACTIVITY [µmol/min/mg]
SPECIFIC ACTIVITY MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
0.59
-
-
-
14
-
-
-
pH OPTIMUM
pH MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
6.8
-
-
-
7.6
-
-
assay at
pH RANGE
pH RANGE MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
6.5
7.9
-
about half-maximal activity at pH 6.5 and 7.9
TEMPERATURE OPTIMUM
TEMPERATURE OPTIMUM MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
additional information
-
-
assay at room temperature
SOURCE TISSUE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
SOURCE
-
proliferating ducts
Manually annotated by BRENDA team
-
hepatocellular carcinoma
Manually annotated by BRENDA team
-
highly expressed in all cholangiocarcinomas
Manually annotated by BRENDA team
-
highly expressed in 4 of 10 hepatocarcinomas, 10-fold activity increase
Manually annotated by BRENDA team
-
cerebellar neuronal cell
Manually annotated by BRENDA team
additional information
-
the enzyme is overexpressed in a wide variety of human malignancies such as breast, hepatic, biliary, colon, pulmonary, pancreatic, and neural origin
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
membrane-associated
Manually annotated by BRENDA team
additional information
-
L-cell extract
-
Manually annotated by BRENDA team
MOLECULAR WEIGHT
MOLECULAR WEIGHT MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
28000
-
-
SDS-PAGE
50700
-
-
sedimentation equilibrium
51030
-
-
MALDI-TOF
52000
-
-
SDS-PAGE, protein with lower molecular weight
56000
-
-
transfected enzyme, SDS-PAGE
56000
-
-
SDS-PAGE, protein with higher molecular weight
86000
-
-
-
86000
-
-
Western blot, full-length protein
110000
-
-
Western blot, post-translational modified protein
SUBUNITS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
dimer
-
homodimer, crystal structure analysis
dimer
Q9NWT6
homodimer
monomer
-
1 * 50700, sedimentation equilibrium
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
phosphoprotein
-
peptide-aspartate beta-dioxygenase can be phosphorylated by glycogen synthase kinase 3beta, and high levels of glycogen synthase kinase 3beta activity result in decrease in peptide-aspartate beta-dioxygenase protein, whereas inhibition of the kinase and/or global caspases increases peptide-aspartate beta-dioxygenase protein. Phosphorylation is higher in ethanol-treated compared with control cells
Crystallization/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
enzyme in complex with peptides of Notch receptor. Significant conformational changes are required in the ankyrin repeat fold of Notch receptor to enable hydroxylation
-
STORAGE STABILITY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
4C, 50 mM Tris-HCl pH 7.2, 1 mg/ml bovine serum albumin, at least 8 weeks stable
-
Purification/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
partial
-
two enzymes, one 52000 Da, the other 56000 Da
-
gel filtration, above 95% purity
-
His6 affinity chromatography
-
Ni2+-NTA garose affinity chromatography
-
recombinant enzyme
-
recombinant enzymes
Q9NWT6
Cloned/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
expressed in wild-type Escherichia coli and in Escherichia coli BL21
-
wild-type and mutant enzymes expressed in Escherichia coli
-
wild-type and mutants expressed in Escherichia coli BL21
-
co-immunization in Mus musculus, thereafter cell fusion of immunized mice splenic lymphocytes with myouse myeloma cells; expression in Escherichia coli DH5alpha
-
expressed in HEK293T cells and in Escherichia coli
-
expressed in Mus musculus liver cells
-
expressed in Sf9 insect cells as His-tag and GST-fusion protein
Q9NWT6
expression in Escherichia coli BL21
-
in vitro transcription and translation in the presence of canine pancreas microsomes
-
transfected into NIH-3T3 cells
-
expression in human CNS neuronal and hepatocellulcar carcinoma cells
-
EXPRESSION
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
overexpression in malignant neoplasms
-
about 2fold increase in expression in double transgenic mice with expression of hepatitis Bx and insulin receptor substrate-1 under a liver-specific promoter
-
ethanol-treated cultures
-
increase after inhibition of GSK-3beta or global caspases
-
ENGINEERING
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
C637A
-
38% activity of wild-type
C644A
-
62% activity of wild-type
C656A
-
100% activity of wild-type
C681A
-
60% activity of wild-type
C696A
-
29% activity of wild-type
G659A
-
21% activity of wild-type
G669A
-
90% activity of wild-type
H667L
-
106% activity of wild-type
H671L
-
16% activity of wild-type
H675D
-
20% activity of wild-type
H675E
-
12% activity of wild-type
H686L
-
9% activity of wild-type
P678V
-
90% activity of wild-type
R682A
-
10% activity of wild-type
R684A
-
8% activity of wild-type
R684K
-
87% activity of wild-type
APPLICATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
analysis
-
isolation of human single-chain Fv fragments directed against human aspartyl-asparaginyl beta-hydroxylase. Antibodies show significant binding to recombinant enzyme in ELISA, tumor cell lines, and tumor tissues. They target different domains of the enzyme. A goat-anti-human IgG saporin conjugate can be delivered into tumor cells by antibody 6-22 and elicits cytotoxicity toward the tumor cells in vitro
medicine
-
insulin-like growth factor-1 stimulates peptide-aspartate beta-dioxygenase protein expression and directional motility. Ethanol reduces the stimulation without inhibition of the mRNA expression, and phosphorylation of the enzyme is higher in ethanol-treated compared with control cells
medicine
-
isolation of human single-chain Fv fragments directed against human aspartyl-asparaginyl beta-hydroxylase. Antibodies show significant binding to recombinant enzyme in ELISA, tumor cell lines, and tumor tissues. They target different domains of the enzyme. A goat-anti-human IgG saporin conjugate can be delivered into tumor cells by antibody 6-22 and elicits cytotoxicity toward the tumor cells in vitro
medicine
-
biomarker to prognosticate non-small cell lung cancer