1.14.11.30: hypoxia-inducible factor-asparagine dioxygenase
This is an abbreviated version!
For detailed information about hypoxia-inducible factor-asparagine dioxygenase, go to the full flat file.
Word Map on EC 1.14.11.30
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1.14.11.30
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prolyl
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hydroxylases
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transactivation
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oxygen-dependent
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ankyrin
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normoxia
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hippel-lindau
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oxygen-sensing
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hif-alpha
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prolyl-hydroxylase
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fih-mediated
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2og-dependent
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hypoxia-sensitive
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dimethyloxalylglycine
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2-oxoglutarate-dependent
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medicine
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drug development
- 1.14.11.30
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prolyl
- hydroxylases
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transactivation
-
oxygen-dependent
- ankyrin
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normoxia
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hippel-lindau
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oxygen-sensing
-
hif-alpha
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prolyl-hydroxylase
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fih-mediated
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2og-dependent
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hypoxia-sensitive
- dimethyloxalylglycine
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2-oxoglutarate-dependent
- medicine
- drug development
Reaction
Synonyms
asparaginyl hydroxylase, asparaginyl-hydroxylase, factor inhibiting HIF, factor inhibiting HIF-1, factor inhibiting hypoxia inducible factor-1alpha, factor-inhibiting HIF, factor-inhibiting hypoxia inducible factor, factor-inhibiting hypoxia-inducible factor, FIH, FIH hydroxylase, HIF asparagine hydroxylase, HIF asparaginyl hydroxylase, HIF hydroxylase, HIF1AN, hypoxia-inducible factor 1-alpha inhibitor, hypoxia-inducible factor asparagine hydroxylase
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General Information
General Information on EC 1.14.11.30 - hypoxia-inducible factor-asparagine dioxygenase
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evolution
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the enzyme belongs to the 2-oxoglutarate- and iron-dependent dioxygenase family of enzymes
malfunction
metabolism
physiological function
additional information
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FIH silencing leads to spacial displacement of the expression pattern of HIF target genes that depend on the C-TAD, such as carbonic anhydrase IX, to more oxygenated areas, whereas overexpression of FIH restricts this pattern to more hypoxic areas. Silencing of gene fih severely reduced in vitro cell proliferation and in vivo tumor growth of LS174 colon adenocarcinoma and A375 melanoma cells. Silencing of fih also significantly increases both the total and phosphorylated forms of the tumor suppressor p53, leading to an increase in its direct target, the cell cycle inhibitor p21. p53-deficient or mutant cells are totally insensitive to FIH expression. FIH activity is essential for tumor growth through the suppression of the p53-p21 axis, the major barrier that prevents cancer progression
malfunction
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silencing FIH under conditions where prolyl hydroxylases, EC 1.14.11.29/30, are inhibited results in increased HIF-1alpha transcriptional activity, but paradoxically decreases HIF-1alpha stability. Residual activity of FIH in hypoxia
malfunction
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the lower enzyme expression in tumor is associated with incomplete tumor encapsulation, vascular invasion, and microvascular density
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HIF transcriptional activity is controlled by the asparaginyl hydroxylase factor inhibiting HIF-1. Hypoxia-induced HIF signalling, mathematical modelling of the pathway, temporal dynamics of the HIF response to hypoxia, and molecular interaction map for the HIF network, overview. The hypoxia inducible factor is switched on and promotes adaptation to hypoxia by upregulating genes involved in angiogenesis, erythropoiesis and glycolysis
metabolism
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hypoxia and oxidant stress can interact functionally as distinct regulators of HIF transcriptional output involving the enzyme. Oxidant stress activates hypoxia pathways through the inactivation of the oxygen-sensing hypoxia-inducible factor prolyl and asparaginyl hydroxylases
metabolism
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optimal HIF-1alpha transcriptional activity requires sequential inhibition of both prolyl- and asparaginyl-hydroxylases
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there are at least two major steps involved in the hypoxic induction of the HIF proteins: (i) inhibition of oxygen-dependent hydroxylation on Pro residues in the oxygen-dependent degradation domain to prevent interaction of HIF with the von Hippel-Lindau tumor suppressor/ubiquitin ligase complex and thus avoid proteasomal destruction, and (ii) inhibition of oxygen-dependent hydroxylation of Asn in the COOH-terminal transactivation domain to promote interaction with the p300/CBP coactivator and induce transcription
physiological function
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FIH modulates the profile of hypoxia-inducible factor downstream genes and of hypoxia-inducible factor target genes in a physiological oxygen gradient: the in vitro spheroid model, overview. FIH enhances tumorigenesis and controls in vitro p53 expression. Factor-inhibiting hypoxia-inducible factor monitors the expression of a spectrum of genes that are dictated by the cell's partial oxygen pressure. This action is mediated by the C-TAD, one of two transactivation domains of the hypoxia-inducible factor
physiological function
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HIF transcriptional activity is controlled by the asparaginyl hydroxylase factor inhibiting HIF-1
physiological function
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key enzyme in activation of the hypoxia-inducible factor (HIF) pathway, a critical step in the transcriptional response to hypoxia, role of FIH in hydroxylase regulation of HIF-1alpha, overview. The enzyme is involved in the HIF-1alpha signalling network, overview. Asparaginyl hydroxylation confers upon HIF-1alpha resistance to proteosomal degradation, but the removal of the asparaginyl hydroxylation step is necessary for HIF-1alpha activity
physiological function
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the enzyme inhibits the hypoxia-inducible factor transcription activation through asparagine hydroxylation
physiological function
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the FIH hydroxylase is a cellular peroxide sensor that modulates HIF transcriptional activity. Cysteine 800 in HIF-1alpha does not regulate N803 or N847 hydroxylation
physiological function
ferritin heavy chain FTH1 directly interacts with FIH. FTH1 facilitates the FIH-mediated Asn803 hydroxylation in hypoxia-inducible factor HIF-1alpha and prevents the recruitment of p300 to HIF-1alpha through the Asn803 hydroxylation. FTH1 represses the transcriptional activity of HIF-1alpha in HCT-116 cells under either normoxic or hypoxic conditions and downregulates the expression of the HIF-1 target genes
physiological function
FIH loss increases oxidative metabolism and also increases glycolytic capacity, this gives rise to an increase in oxygen consumption. The loss of FIH acts to accelerate the cellular metabolic response to hypoxia. FIH suppresses hypoxia-induced mitochondrial reactive oxygen species production and FIH loss accelerates the effects of hypoxic exposure on mitochondria
physiological function
the enzyme controls HIF transcriptional activity in an oxygen-dependent manner
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HIF asparaginyl hydroxylase is strikingly more sensitive to peroxide than the HIF prolyl hydroxylases, EC 1.14.11.29. Inhibition of FIH by peroxide persists in hypoxia
additional information
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modeling of the dynamic regulation of HIF-1alpha transcriptional activity by the hydroxylase. HIF-1alpha stabilisation and transcriptional activity is dependent on oxygen tension
additional information
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PHD, EC 1.14.11.29, has a higher affinity for oxygen than FIH