Information on EC 1.14.11.30 - hypoxia-inducible factor-asparagine dioxygenase

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The expected taxonomic range for this enzyme is: Homo sapiens

EC NUMBER
COMMENTARY hide
1.14.11.30
-
RECOMMENDED NAME
GeneOntology No.
hypoxia-inducible factor-asparagine dioxygenase
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REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
hypoxia-inducible factor-L-asparagine + 2-oxoglutarate + O2 = hypoxia-inducible factor-(3S)-3-hydroxy-L-asparagine + succinate + CO2
show the reaction diagram
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
hypoxia-inducible factor-L-asparagine, 2-oxoglutarate:oxygen oxidoreductase (4-hydroxylating)
Contains iron, and requires ascorbate. Catalyses hydroxylation of an asparagine in the C-terminal transcriptional activation domain of HIF-alpha, the alpha subunit of the transcriptional regulator HIF (hypoxia-inducible factor), which reduces its interaction with the transcriptional coactivator protein p300. The requirement of oxygen for the hydroxylation reaction enables animals to respond to hypoxia.
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
evolution
-
the enzyme belongs to the 2-oxoglutarate- and iron-dependent dioxygenase family of enzymes
malfunction
metabolism
physiological function
additional information
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
DESGLPQLTSYDCEVNAPI + 2-oxoglutarate + O2
?
show the reaction diagram
-
hypoxia-inducible factor-1alpha peptide 788-806. 9% of the activity obtained with the 35-amino-acid HIF-1alpha peptide DES35 (DESGLPQLTSYDCEVNAPIQGSRNLLQGEELLRAL)
-
-
?
DESGLPQLTSYDCEVNAPIQGSR + 2-oxoglutarate + O2
?
show the reaction diagram
-
hypoxia-inducible factor-1alpha peptide 788-810. 15% of the activity obtained with the 35-amino-acid HIF-1alpha peptide DES35 (DESGLPQLTSYDCEVNAPIQGSRNLLQGEELLRAL)
-
-
?
DESGLPQLTSYDCEVNAPIQGSRNLLQ + 2-oxoglutarate + O2
?
show the reaction diagram
-
hypoxia-inducible factor-1alpha peptide 788-814. 37% of the activity obtained with the 35-amino-acid HIF-1alpha peptide DES35 (DESGLPQLTSYDCEVNAPIQGSRNLLQGEELLRAL)
-
-
?
DESGLPQLTSYDCEVNAPIQGSRNLLQGEEL + 2-oxoglutarate + O2
?
show the reaction diagram
-
hypoxia-inducible factor-1alpha peptide 788-818. 26% of the activity obtained with the 35-amino-acid HIF-1alpha peptide DES35 (DESGLPQLTSYDCEVNAPIQGSRNLLQGEELLRAL)
-
-
?
DESGLPQLTSYDCEVNAPIQGSRNLLQGEELLRAL + 2-oxoglutarate + O2
?
show the reaction diagram
-
hypoxia-inducible factor-1alpha peptide 788-822
-
-
?
ESYLLPELTRYDCEVNVPVLGSSTLLQGGDLLRAL + 2-oxoglutarate + O2
?
show the reaction diagram
-
hypoxia-inducible factor-2alpha peptide 832-857. 7% of the activity obtained with the 35-amino-acid HIF-1alpha peptide DES35 (DESGLPQLTSYDCEVNAPIQGSRNLLQGEELLRAL)
-
-
?
hypoxia-inducible factor-L-asparagine + 2-oxoglutarate + O2
hypoxia-inducible factor-(3S)-3-hydroxy-L-asparagine + succinate + CO2
show the reaction diagram
hypoxia-inducible factor-L-asparagine peptide + 2-oxoglutarate + O2
hypoxia-inducible factor-(3S)-3-hydroxy-L-asparagine peptide + succinate + CO2
show the reaction diagram
-
39-residue peptide corresponding to HIF-1alpha788-826 mutant C800A
hydroxylation at Asn803
-
?
hypoxia-inducible factor1alpha C-terminal oxygen dependent degradation domain-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor1alpha C-terminal oxygen dependent degradation domain-trans-4-hydroxy-L-proline + succinate + CO2
show the reaction diagram
-
-
-
-
?
hypoxia-inducible factor1alpha N-terminal oxygen dependent degradation domain-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor1alpha N-terminal oxygen dependent degradation domain-trans-4-hydroxy-L-proline + succinate + CO2
show the reaction diagram
-
-
-
-
?
hypoxia-inducible factor2alpha C-terminal oxygen dependent degradation domain-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor2alpha C-terminal oxygen dependent degradation domain-trans-4-hydroxy-L-proline + succinate + CO2
show the reaction diagram
-
-
-
-
?
hypoxia-inducible factor2alpha N-terminal oxygen dependent degradation domain-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor2alpha N-terminal oxygen dependent degradation domain-trans-4-hydroxy-L-proline + succinate + CO2
show the reaction diagram
-
-
-
-
?
LTRYDCEVNVPVLGSSTLL + O2
?
show the reaction diagram
-
hypoxia-inducible factor-2alpha peptide 839-866. 1% of the activity obtained with the 35-amino-acid HIF-1alpha peptide DES35 (DESGLPQLTSYDCEVNAPIQGSRNLLQGEELLRAL)
-
-
?
LTSYDCEVNAPIQGSRNLL + 2-oxoglutarate + O2
?
show the reaction diagram
-
hypoxia-inducible factor-1alpha peptide 795-813. 4% of the activity obtained with the 35-amino-acid HIF-1alpha peptide DES35 (DESGLPQLTSYDCEVNAPIQGSRNLLQGEELLRAL)
-
-
?
PSDLACRLLGQSMDESGLPQLTSYDCEVNAPIQGSRNLLQGEELLRALDQVN + 2-oxoglutarate + O2
?
show the reaction diagram
rabankyrin + 2-oxoglutarate + O2
trihydroxy-rabankyrin + succinate + CO2
show the reaction diagram
-
hydroxylation at N316, N485 and N649
-
-
?
additional information
?
-
-
the subtrate contains a C-terminal and a N-terminal oxygen-dependent degradation domain, as well as a C-terminal transactivation domain
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-
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NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
hypoxia-inducible factor-L-asparagine + 2-oxoglutarate + O2
hypoxia-inducible factor-(3S)-3-hydroxy-L-asparagine + succinate + CO2
show the reaction diagram
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
2,3-dihydroxypyridine
-
-
2-hydroxypyridine 1-oxide
-
-
3,4-dihydroxybenzoate
-
-
3-cyano-6-methyl-2(H)-pyridinone
-
-
3-hydroxy-1,2-dimethyl-4(1H)-pyridinone
-
-
3-hydroxy-2-methyl-4-pyrone
-
-
4-Methylcatechol
-
-
4-nitrocatechol
-
-
4-tert-butylcatechol
-
-
5-hydroxy-2-hydroxymethyl-4-pyrone
-
-
5-hydroxy-4-oxo-4H-pyran-2-carboxylic acid
-
-
Co2+
-
-
H2O2
-
peroxide rapidly inhibits hydroxlation of diverse FIH substrates and inhibits FIH in a range of cell types. Preferential inhibition of N803-hydroxylation compared with P402/P564 hydroxylation by PHDs, EC 1.14.11.29. Cysteine 800 in HIF-1alpha does not regulate N803 or N847 hydroxylation. FIH activity is not restored by exogenous Fe2+
N-(methoxyoxoacetyl)-glycine methyl ester
-
a pan-hydroxylase inhibitor, in vitro and in vivo inhibition
N-oxaloylglycine
-
-
oxalylglycine
-
-
Pyridine-2,4-dicarboxylate
-
-
Pyridine-2,5-dicarboxylate
-
-
Zn2+
-
-
additional information
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
ascorbate
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.01 - 0.025
2-oxoglutarate
0.09
O2
-
pH 7.8, 37°C. The Km of FIH for O2 is about 40% of its atmospheric concentration, Km-value is determined using soluble extracts of cells expressing enzyme-FLAGHis
0.01
PSDLACRLLGQSMDESGLPQLTSYDCEVNAPIQGSRNLLQGEELLRALDQVN
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pH 7.4, 37°C
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additional information
additional information
-
steady-state kinetic analysis and substrate selectivity for hypoxia-inducible factor and 2-oxoglutarate
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
additional information
additional information
Homo sapiens
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the catalytic center activities obtained for the enzyme purified by two alternative procedures are 85-135 and 70-120 mol/mol/min, respectively
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Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.01
3,4-dihydroxybenzoate
-
pH 7.8, 37°C, Ki-value is determined using soluble extracts of cells expressing enzyme-FLAGHis
0.1
DESGLPQLTSYDCEVNAPIQGSRNLLQGEELLRAL
-
pH 7.8, 37°C, Ki-value is determined using soluble extracts of cells expressing enzyme-FLAGHis
0.16
ESYLLPELTRYDCEVNVPVLGSSTLLQGGDLLRAL
-
pH 7.8, 37°C, Ki-value is determined using soluble extracts of cells expressing enzyme-FLAGHis
0.002
oxalylglycine
-
pH 7.8, 37°C, Ki-value is determined using soluble extracts of cells expressing enzyme-FLAGHis
0.1
PSDLACRLLGQSMDESGLPQLTSYDCEVNAPIQGSRNLLQGEELLRALDQVN
-
pH 7.8, 37°C, Ki-value is determined using soluble extracts of cells expressing enzyme-FLAGHis
-
0.03
Pyridine-2,4-dicarboxylate
-
pH 7.8, 37°C, Ki-value is determined using soluble extracts of cells expressing enzyme-FLAGHis
0.05
Pyridine-2,5-dicarboxylate
-
pH 7.8, 37°C, Ki-value is determined using soluble extracts of cells expressing enzyme-FLAGHis
additional information
additional information
-
the Ki-value for 3-hydroxypyridine-2-carbonylglycine and N-((3-Hydroxy-6-chloroquinolin-2-yl)carbonyl)glycine are above 0.3 mM
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.075
2,3-dihydroxypyridine
Homo sapiens
-
pH 7.0, 37°C
0.01
2-hydroxypyridine 1-oxide
Homo sapiens
-
pH 7.0, 37°C
1
3-cyano-6-methyl-2(H)-pyridinone
Homo sapiens
-
above, pH 7.0, 37°C
0.03
3-hydroxy-1,2-dimethyl-4(1H)-pyridinone
Homo sapiens
-
pH 7.0, 37°C
0.07
3-hydroxy-2-methyl-4-pyrone
Homo sapiens
-
above, pH 7.0, 37°C
0.05
4-Methylcatechol
Homo sapiens
-
pH 7.0, 37°C
0.01
4-nitrocatechol
Homo sapiens
-
pH 7.0, 37°C
0.12
4-tert-butylcatechol
Homo sapiens
-
pH 7.0, 37°C
0.17
5-hydroxy-2-hydroxymethyl-4-pyrone
Homo sapiens
-
pH 7.0, 37°C
0.05
5-hydroxy-4-oxo-4H-pyran-2-carboxylic acid
Homo sapiens
-
pH 7.0, 37°C
0.01
Co2+
Homo sapiens
-
-
0.025
N-oxaloylglycine
Homo sapiens
-
-
0.01
Zn2+
Homo sapiens
-
-
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7
-
assay at
7.4
-
assay at
7.5
-
assay at
7.8
-
assay at
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
25
-
assay at
37
-
assay at
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
-
melanoma cells
Manually annotated by BRENDA team
-
colon adenocarcinoma cells
Manually annotated by BRENDA team
PDB
SCOP
CATH
ORGANISM
UNIPROT
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
dimer
-
-
Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
recombinant dox-inducible FLAG-tagged FIH from U2-OS cells by immunoaffinity chromatography
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recombinant GST-tagged PHD2 by glutathiione affinity chromatography
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recombinant His- and MBP-tagged FIH from Escherichia coli strain BL21(DE3)pRR692 by nickel affinity and anion exchange chromatography
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Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
expression of dox-inducible FLAG-tagged FIH in U2-OS cells
-
expression of N-terminally His-tagged FIH-1 in Escherichia coli strain BL21(DE3)
-
HIF asparaginyl hydroxylase (FIH), His-FIH, FIH-FLAGHis, FIH-V5His, and GST-FIH polypeptides are expressed in Spodoptera frugiperda Sf9 cells
-
recombinant expression of GST-tagged PHD2
-
ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
-
FIH silencing by siRNA
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
drug development
-
the unique function of FIH makes it a prime target for selective inhibition leading to regulatory control of diseases such as cancer and stroke
medicine
-
the high constitutive activities of the proteins with both Pro and Asn substitutions confirm that the relevant prolyl and asparaginyl hydroxylases are attractive targets for therapeutic regulation of hypoxia-inducible factor-1alpha and hypoxia-inducible factor-2alpha