Information on EC 1.14.11.29 - hypoxia-inducible factor-proline dioxygenase

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The expected taxonomic range for this enzyme is: Coelomata

EC NUMBER
COMMENTARY
1.14.11.29
-
RECOMMENDED NAME
GeneOntology No.
hypoxia-inducible factor-proline dioxygenase
-
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2 = hypoxia-inducible factor-trans-4-hydroxy-L-proline + succinate + CO2
show the reaction diagram
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
hypoxia-inducible factor-L-proline, 2-oxoglutarate:oxygen oxidoreductase (4-hydroxylating)
Contains iron, and requires ascorbate. Specifically hydroxylates a proline residue in HIF-alpha, the alpha subunit of the transcriptional regulator HIF (hypoxia-inducible factor), which targets HIF for proteasomal destruction. The requirement of oxygen for the hydroxylation reaction enables animals to respond to hypoxia.
SYNONYMS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
factor inhibiting HIF
-
-
HIF hydroxylase
Q96KS0, Q9GZT9, Q9H6Z9
-
HIF prolyl
Q96KS0
-
HIF prolyl hydroxylase
-
-
HIF prolyl hydroxylase
Q9GZT9
-
HIF-1alpha PHD3
-
-
HIF-1alpha prolyl hydroxylase 3
-
-
HIF-alpha prolyl-hydroxylase
-
-
HIF-P4H-1
-
-
HIF-P4H-2
Q9GZT9
-
HIF-P4H-3
Q9H6Z9
-
HIF-PH
-
-
HIF-prolyl hydroxylase domain 2
-
-
HIF-prolyl hydroxylase-2
-
-
HPH-1
-
-
HPH-2
Q9GZT9
-
HPH-3
Q96KS0
-
PHD1
Q96KS0
-
PHD2
Q9GZT9
-
PHD3
Q9H6Z9
-
proline hydroxylase domain 2
-
-
prolyl hydroxylase
-
-
prolyl hydroxylase domain
-
-
prolyl hydroxylase domain
Q96KS0, Q9GZT9, Q9H6Z9
-
prolyl hydroxylase-2
-
-
ORGANISM
COMMENTARY
LITERATURE
SEQUENCE CODE
SEQUENCE DB
SOURCE
HIF-P4H-2
SwissProt
Manually annotated by BRENDA team
HIF-P4H-3
SwissProt
Manually annotated by BRENDA team
HPH-2
SwissProt
Manually annotated by BRENDA team
HPH-3
SwissProt
Manually annotated by BRENDA team
isozyme PHD1
SwissProt
Manually annotated by BRENDA team
isozyme PHD2
SwissProt
Manually annotated by BRENDA team
isozyme PHD2
-
-
Manually annotated by BRENDA team
isozyme PHD3
SwissProt
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
evolution
Q96KS0, Q9GZT9, Q9H6Z9
the enzyme belongs to the of the 2-oxoglutarate- and iron-dependent dioxygenase family of enzymes; the enzyme belongs to the of the 2-oxoglutarate- and iron-dependent dioxygenase family of enzymes; the enzyme belongs to the of the 2-oxoglutarate- and iron-dependent dioxygenase family of enzymes
evolution
-
PHD3 belongs to Fe2+/2-oxoglutarate-dependent oxygenase family
malfunction
-
silencing FIH, EC 1.14.11.30, under conditions where prolyl hydroxylase, is inhibited results in increased HIF-1alpha transcriptional activity, but paradoxically decreases HIF-1alpha stability
metabolism
-
HIF protein stability is controlled by the oxygen sensing prolyl hydroxylase domain enzymes. 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 upregulatinggenes involved in angiogenesis, erythropoiesis and glycolysis
metabolism
-
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
physiological function
-
HIF (hypoxia-inducible factor) is a transcription factor that plays a pivotal role in cellular adaptation to changes in oxygen availability. In the presence of oxygen, HIF is targeted for destruction by an E3 ubiquitin ligase containing the von Hippel-Lindau tumor suppressor protein (pVHL). Human pVHL binds to a short HIF-derived peptide when a conserved proline residue at the core of this peptide is hydroxylated. This protein modifiation may play a key role in mammalian oxygen sensing
physiological function
-
hypoxia-inducible factor (HIF) is a transcriptional complex that plays a central role in the regulation of gene expression by oxygen. In oxygenated and iron replete cells, HIF-alpha subunits are rapidly destroyed by a mechanism that involves ubiquitylation by the von Hippel-Lindau tumor suppressor (pVHL) E3 ligase complex. This process is suppressed by hypoxia and iron chelation, allowing transcriptional activation. The interaction between human pVHL and a specific domain of the HIF-1alpha subunit is regulated through hydroxylation of a proline residue (HIF-1alpha P564) by HIF-alpha prolyl-hydroxylase (HIF-PH). HIF-PH functions directly as a cellular oxygen sensor. Exposure of cells to dimethyl-oxalylglycine, that penetrates cells readily, results in rapid induction of HIF-1alpha
physiological function
Q96KS0, Q9GZT9
in cultured mammalian cells, inappropriate accumulation of hypoxia-inducible factor caused by forced expression of the hypoxia-inducible factor-1alpha subunit under normoxic conditions is attenuated by coexpression of HIF prolyl hydroxylase. Suppression of HIF prolyl hydroxylase in cultured Drosophila melanogaster cells by RNA interference results in elevated expression of a hypoxia-inducible gene (LDH, encoding lactate dehydrogenase) under normoxic conditions. HIF prolyl hydroxylase is an essential component of the pathway through which cells sense oxygen; in cultured mammalian cells, inappropriate accumulation of hypoxia-inducible factor caused by forced expression of the hypoxia-inducible factor-1alpha subunit under normoxic conditions is attenuated by coexpression of HIF prolyl hydroxylase. Suppression of HIF prolyl hydroxylase in cultured Drosophila melanogaster cells by RNA interference results in elevated expression of a hypoxia-inducible gene (LDH, encoding lactate dehydrogenase) under normoxic conditions. HIF prolyl hydroxylase is an essential component of the pathway through which cells sense oxygen; in cultured mammalian cells, inappropriate accumulation of hypoxia-inducible factor caused by forced expression of the hypoxia-inducible factor-1alpha subunit under normoxic conditions is attenuated by coexpression of HIF prolyl. Suppression of HIF prolyl in cultured Drosophila melanogaster cells by RNA interference results in elevated expression of a hypoxia-inducible gene (LDH, encoding lactate dehydrogenase) under normoxic conditions. HIF prolyl is an essential component of the pathway through which cells sense oxygen
physiological function
Q96KS0, Q9GZT9, Q9H6Z9
the prolyl hydroxylases control the abundance of hypoxia-inducible factor through oxygen-dependent hydroxylation of specific proline residues in hypoxia-inducible factor proteins, triggering subsequent ubiquitination and proteasomal degradation; the prolyl hydroxylases control the abundance of hypoxia-inducible factor through oxygen-dependent hydroxylation of specific proline residues in hypoxia-inducible factor proteins, triggering subsequent ubiquitination and proteasomal degradation; the prolyl hydroxylases control the abundance of hypoxia-inducible factor through oxygen-dependent hydroxylation of specific proline residues in hypoxia-inducible factor proteins, triggering subsequent ubiquitination and proteasomal degradation. Differential regulation of HIF1alpha and HIF2alpha at the NODDD site by PHD2
physiological function
-
HIF transcriptional activity is controlled by the asparaginyl hydroxylase factor inhibiting HIF-1, FIH
physiological function
-
key enzyme in activation of the hypoxia-inducible factor (HIF) pathway, a critical step in the transcriptional response to hypoxia. The enzyme is involved in the HIF-1alpha signalling network, overview
physiological function
-
prolyl hydroxylases inactivate hypoxia-inducible factor-1alpha by hydroxylation, PHD isozymes play an integral role in oxygen homeostasis. HIF-1alpha is an important regulation factor in the histiocyte under hypoxia conditions
physiological function
-
HIF prolyl-4-hydroxylase 2 regulates the hypoxia inducible transcription factor by hydroxylating two conserved prolyl residues in N-terminal oxygen degradation domain and C-terminal oxygen degradation domain of HIF-1alpha, the enzyme PHD2 prefers the C-terminal oxygen degradation domain by 20fold over the N-terminal, loop closure is the dominant contributor to substrate selectivity in PHD2
metabolism
-
optimal HIF-1alpha transcriptional activity requires sequential inhibition of both prolyl- and asparaginyl-hydroxylases
additional information
-
PHD has a higher affinity for oxygen than FIH, EC 1.14.11.30
additional information
-
HIF asparaginyl hydroxylase, EC 1.14.11.30, is strikingly more sensitive to peroxide than the HIF prolyl hydroxylases
additional information
-
modeling of the dynamic regulation of HIF-1alpha transcriptional activity by the hydroxylase. HIF-1alpha stabilisation and transcriptional activity is dependent on oxygen tension
SUBSTRATE
PRODUCT                      
REACTION DIAGRAM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
DALDLEMLAPYISMDDDFQL + 2-oxoglutarate + O2
?
show the reaction diagram
-, Q9GZT9, Q9H6Z9
a HIF-3alpha peptide. Vmax is 120% of the activity with DLDLEMLAPYIPMDDDFQL
-
-
?
DALDLEMLAPYISMDDDFQL + 2-oxoglutarate + O2
DALDLEMLA-((4R)-4-hydroxy-L-proline)-YISMDDDFQL + succinate + CO2
show the reaction diagram
-, Q9GZT9, Q9H6Z9
a HIF-3alpha peptide. Vmax is 120% of the activity with DLDLEMLAPYIPMDDDFQL
-
-
?
DALDLEMLAPYISMDDDFQL + 2-oxoglutarate + O2
DALDLEMLA-((4R)-4-hydroxy-L-proline)-YISMDDDFQL + succinate + CO2
show the reaction diagram
-, Q9GZT9, Q9H6Z9
a HIF-3alpha peptide. Vmax is 150% of the activity with DLDLEMLAPYIPMDDDFQL
-
-
?
DALTLLAPAAGDTIISLFG + 2-oxoglutarate + O2
DALTLLA-((4R)-4-hydroxy-L-proline)-AAGDTIISLFG + succinate + CO2
show the reaction diagram
-, Q9GZT9, Q9H6Z9
N-terminal hydroxylation site of HIF-1alpha, Vmax is 100% of the activity with DLDLEMLAPYIPMDDDFQL
-
-
?
DALTLLAPAAGDTIISLFG + 2-oxoglutarate + O2
DALTLLA-((4R)-4-hydroxy-L-proline)-AAGDTIISLFG + succinate + CO2
show the reaction diagram
-, Q9GZT9, Q9H6Z9
N-terminal hydroxylation site of HIF-1alpha, Vmax is 60% of the activity with DLDLEMLAPYIPMDDDFQL
-
-
?
DLDLEMLAPAIPMDDDFQL + 2-oxoglutarate + O2
DLDLEMLA-((4R)-4-hydroxy-L-proline)-AIPMDDDFQL + succinate + CO2
show the reaction diagram
-, Q9GZT9, Q9H6Z9
Vmax is 100% of the activity with DLDLEMLAPYIPMDDDFQL
-
-
?
DLDLEMLAPAIPMDDDFQL + 2-oxoglutarate + O2
DLDLEMLA-((4R)-4-hydroxy-L-proline)-AIPMDDDFQL succinate + CO2
show the reaction diagram
-, Q9GZT9, Q9H6Z9
Vmax is 100% of the activity with DLDLEMLAPYIPMDDDFQL
-
-
?
DLDLEMLAPGIPMDDDFQL + 2-oxoglutarate + O2
DLDLEMLA-((4R)-4-hydroxy-L-proline)-GIPMDDDFQL + succinate + CO2
show the reaction diagram
-, Q9GZT9, Q9H6Z9
Vmax is 100% of the activity with DLDLEMLAPYIPMDDDFQL
-
-
?
DLDLEMLAPYIPMD + 2-oxoglutarate + O2
DLDLEMLA-((4R)-4-hydroxy-L-proline)-YIPMD + succinate + CO2
show the reaction diagram
-, Q9GZT9, Q9H6Z9
Vmax is 100% of the activity with DLDLEMLAPYIPMDDDFQL
-
-
?
DLDLEMLAPYIPMDD + 2-oxoglutarate + O2
DLDLEMLA-((4R)-4-hydroxy-L-proline)-YIPMDD + succinate + CO2
show the reaction diagram
-, Q9GZT9, Q9H6Z9
Vmax is 100% of the activity with DLDLEMLAPYIPMDDDFQL
-
-
?
DLDLEMLAPYIPMDDDF + 2-oxoglutarate + O2
DLDLEMLA-((4R)-4-hydroxy-L-proline)-YIPMDDDF + succinate + CO2
show the reaction diagram
-, Q9GZT9, Q9H6Z9
Vmax is 100% of the activity with DLDLEMLAPYIPMDDDFQL
-
-
?
DLDLEMLAPYIPMDDDFQL + 2-oxoglutarate + O2
DLDLEMLA-((4R)-4-hydroxy-L-proline)-YIPMDDDFQL + succinate + CO2
show the reaction diagram
-, Q9GZT9, Q9H6Z9
-
-
-
?
DLDLEMLAPYIPMDDDFQLRSFDQ + 2-oxoglutarate + O2
DLDLEMLA-((4R)-4-hydroxy-L-proline)-YIPMDDDFQLRSFDQ + succinate + CO2
show the reaction diagram
-, Q9GZT9, Q9H6Z9
Vmax is 100% of the activity with DLDLEMLAPYIPMDDDFQL
-
-
?
DLEMLAPYIPMDDDFQL + 2-oxoglutarate + O2
DLDLEMLA-((4R)-4-hydroxy-L-proline)-YIPMDDDFQL + succinate + CO2
show the reaction diagram
-, Q9GZT9, Q9H6Z9
Vmax is 100% of the activity with DLDLEMLAPYIPMDDDFQL
-
-
?
DLEMLAPYIPMDDDFQL + 2-oxoglutarate + O2
DLEMLA-((4R)-4-hydroxy-L-proline)-YIPMDDDFQL + succinate + CO2
show the reaction diagram
-, Q9GZT9, Q9H6Z9
Vmax is 100% of the activity with DLDLEMLAPYIPMDDDFQL
-
-
?
EEPDLSCLAPFVDTYDMMQM + 2-oxoglutarate + O2
?
show the reaction diagram
-, Q9GZT9, Q9H6Z9
hydroxylation site of Caenorhabditis elegans HIF-alpha. Vmax is 60% of the activity with DLDLEMLAPYIPMDDDFQL
-
-
?
EEPDLSCLAPFVDTYDMMQM + 2-oxoglutarate + O2
?
show the reaction diagram
-, Q9GZT9, Q9H6Z9
hydroxylation site of Caenorhabditis elegans HIF-alpha. Vmax is 80% of the activity with DLDLEMLAPYIPMDDDFQL
-
-
?
ELDLETLAPYIPMDGEDFQ + 2-oxoglutarate + O2
?
show the reaction diagram
-, Q9GZT9, Q9H6Z9
C-terminal hydroxylation site of HIF-2alpha. Vmax is 100% of the activity with DLDLEMLAPYIPMDDDFQL
-
-
?
ELDLETLAPYIPMDGEDFQ + 2-oxoglutarate + O2
?
show the reaction diagram
-, Q9GZT9, Q9H6Z9
C-terminal hydroxylation site of HIF-2alpha. Vmax is 70% of the activity with DLDLEMLAPYIPMDDDFQL
-
-
?
ELDLETLAPYIPMDGEDFQ + 2-oxoglutarate + O2
ELDLETLA-((4R)-4-hydroxy-L-proline)-YIPMDGEDFQ + succinate + CO2
show the reaction diagram
-, Q9GZT9, Q9H6Z9
C-terminal hydroxylation site of HIF-2alpha. Vmax is 80% of the activity with DLDLEMLAPYIPMDDDFQL
-
-
?
EMLAPYIPMDD + 2-oxoglutarate + O2
EMLA-((4R)-4-hydroxy-L-proline)-YIPMDD + succinate + CO2
show the reaction diagram
-, Q9GZT9, Q9H6Z9
Vmax is 30% of the activity with DLDLEMLAPYIPMDDDFQL
-
-
?
EMLAPYIPMDDDFQL + 2-oxoglutarate + O2
EMLA-((4R)-4-hydroxy-L-proline)-YIPMDDDFQL + succinate + CO2
show the reaction diagram
-, Q9GZT9, Q9H6Z9
Vmax is 100% of the activity with DLDLEMLAPYIPMDDDFQL
-
-
?
EMLAPYIPMDDDFQL + 2-oxoglutarate + O2
EMLA-((4R)-4-hydroxy-L-proline)-YIPMDDDFQL + succinate + CO2
show the reaction diagram
-, Q9GZT9, Q9H6Z9
Vmax is 80% of the activity with DLDLEMLAPYIPMDDDFQL
-
-
?
EPEELAQLAPTPGDAIISLD + 2-oxoglutarate + O2
?
show the reaction diagram
-, Q9GZT9, Q9H6Z9
N-terminal hydroxylation site of HIF-2alpha. Vmax is 30% of the activity with DLDLEMLAPYIPMDDDFQL
-
-
?
EPEELAQLAPTPGDAIISLD + 2-oxoglutarate + O2
?
show the reaction diagram
-, Q9GZT9, Q9H6Z9
N-terminal hydroxylation site of HIF-2alpha. Vmax is 70% of the activity with DLDLEMLAPYIPMDDDFQL
-
-
?
EPEELAQLAPTPGDAIISLD + 2-oxoglutarate + O2
?
show the reaction diagram
-, Q9GZT9, Q9H6Z9
N-terminal hydroxylation site of HIF-2alpha. Vmax is 80% of the activity with DLDLEMLAPYIPMDDDFQL
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-(4R)-4-hydroxy-L-proline + succinate + CO2
show the reaction diagram
-, Q9GZT9, Q9H6Z9
-
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-(4R)-4-hydroxy-L-proline + succinate + CO2
show the reaction diagram
-
-
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-(4R)-4-hydroxy-L-proline + succinate + CO2
show the reaction diagram
-
HIF (hypoxia-inducible factor) is a transcription factor that plays a pivotal role in cellular adaptation to changes in oxygen availability. In the presence of oxygen, HIF is targeted for destruction by an E3 ubiquitin ligase containing the von Hippel-Lindau tumor suppressor protein (pVHL). Human pVHL binds to a short HIF-derived peptide when a conserved proline residue at the core of this peptide is hydroxylated. This protein modifiation may play a key role in mammalian oxygen sensing
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-(4R)-4-hydroxy-L-proline + succinate + CO2
show the reaction diagram
-
hypoxia-inducible factor (HIF) is a transcriptional complex that plays a central role in the regulation of gene expression by oxygen. In oxygenated and iron replete cells, HIF-alpha subunits are rapidly destroyed by a mechanism that involves ubiquitylation by the von Hippel-Lindau tumor suppressor (pVHL) E3 ligase complex. This process is suppressed by hypoxia and iron chelation, allowing transcriptional activation. The interaction between human pVHL and a specific domain of the HIF-1alpha subunit is regulated through hydroxylation of a proline residue (HIF-1alpha P564) by HIF-alpha prolyl-hydroxylase (HIF-PH). HIF-PH functions directly as a cellular oxygen sensor
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-(4R)-4-hydroxy-L-proline + succinate + CO2
show the reaction diagram
Q96KS0, Q9GZT9
mammalian cells respond to changes in oxygen availability through a conserved pathway that is regulated by the hypoxia-inducible factor (HIF). The alpha subunit of the hypoxia-inducible factor is targeted for degradation under normoxic conditions by a ubiquitin-ligase complex that recognizes a hydroxylated proline residue in hypoxia-inducible factor. HIF prolyl hydroxylase is responsible for this posttranslational modification
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-(4R)-4-hydroxy-L-proline + succinate + CO2
show the reaction diagram
Q96KS0, Q9GZT9
mammalian cells respond to changes in oxygen availability through a conserved pathway that is regulated by the hypoxia-inducible factor (HIF). The alpha subunit of the hypoxia-inducible factor is targeted for degradation under normoxic conditions by a ubiquitin-ligase complex that recognizes a hydroxylated proline residue in hypoxia-inducible factor. HIF prolyl is responsible for this posttranslational modification
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-(4R)-4-hydroxy-L-proline + succinate + CO2
show the reaction diagram
Q96KS0, Q9GZT9
target proline residue: Pro564 in human HIF-alpha. A control peptide in which the target proline residue is replaced by alanine is not modified
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-(4R)-4-hydroxy-L-proline + succinate + CO2
show the reaction diagram
Q96KS0, Q9GZT9
target proline residue: Pro564 in human HIF-alpha. A control peptide in which the target proline residue is replaced by alanine is not modified. The endogenous HIF prolyl hydroxylase, HPH-1 generates by in vitro transcription/translation does not modify peptides containing the L562A, A563G, or Y565A mutations. However, a peptide containing the Pro567 to Gly mutation is an equal, if not better, substrate for the human HPH enzymes
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-(4R)-4-hydroxy-L-proline + succinate + CO2
show the reaction diagram
Q96KS0, Q9GZT9
target proline residue: Pro564 in human HIF-alpha. A control peptide in which the target proline residue is replaced by alanine is not modified. The recombinant HPH-2 purified from Escherichia coli does not modify peptides containing the L562A, A563G, or Y565A mutations. However, a peptide containing the Pro567 to Gly mutation is an equal, if not better, substrate for the human HPH enzymes
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-trans-4-hydroxy-L-proline + succinate + CO2
show the reaction diagram
-
-
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-trans-4-hydroxy-L-proline + succinate + CO2
show the reaction diagram
Q96KS0, Q9GZT9, Q9H6Z9
-
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-trans-4-hydroxy-L-proline + succinate + CO2
show the reaction diagram
Q96KS0, Q9GZT9, Q9H6Z9
HIF1alpha is a better substrate than HIF2alpha for PHD2
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-trans-4-hydroxy-L-proline + succinate + CO2
show the reaction diagram
-
PHD enzymes hydroxylates HIF-alpha at prolyl residues present in the transcriptional activation domain N-TAD
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-trans-4-hydroxy-L-proline + succinate + CO2
show the reaction diagram
-
PHD2 hydroxylates Pro402 and/or Pro564 of HIF-1alpha
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-trans-4-hydroxy-L-proline + succinate + CO2
show the reaction diagram
Q96KS0, Q9GZT9, Q9H6Z9
differential regulation of HIF1alpha and HIF2alpha at the N-terminal oxygen-dependent degradation domain site by PHD2
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-trans-4-hydroxy-L-proline + succinate + CO2
show the reaction diagram
-
hydroxylation at P402 and P564
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-trans-4-hydroxy-L-proline + succinate + CO2
show the reaction diagram
-
hydroxylation of the proline residue in the HIF-1alpha (556-574) peptide substrate, sequence of residues 556-574: DLDLEMLAPYIPMDDDFQL
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-trans-4-hydroxy-L-proline + succinate + CO2
show the reaction diagram
Q96KS0, Q9GZT9, Q9H6Z9
the HIF1alpha C-terminal oxygen-dependent degradation domain is highly preferred for hydroxylation, no N-terminal oxygen-dependent degradation domain hydroxylation for both HIF2alpha and HIF1alpha
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-trans-4-hydroxy-L-proline + succinate + CO2
show the reaction diagram
Q96KS0, Q9GZT9, Q9H6Z9
the PHD1 reaction at the N-terminal oxygen-dependent degradation domain site shows low level hydroxylation
-
-
?
hypoxia-inducible factor-L-proline peptide + 2-oxoglutarate + O2
hypoxia-inducible factor-trans-4-hydroxy-L-proline peptide + succinate + CO2
show the reaction diagram
-
peptide substrate is a peptide derived from the natural sequence of HIF-1alpha residues 556-574
hydroxylation at Pro564
-
?
hypoxia-inducible factor-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-(3S)-3-hydroxy-proline + succinate + CO2
show the reaction diagram
-
HIF-1alpha
-
-
?
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
Q96KS0, Q9GZT9, Q9H6Z9
-
-
-
?
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
Q96KS0, Q9GZT9, Q9H6Z9
low activity
-
-
?
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
Q96KS0, Q9GZT9, Q9H6Z9
-
-
-
?
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
Q96KS0, Q9GZT9, Q9H6Z9
low activity
-
-
?
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
Q96KS0, Q9GZT9, Q9H6Z9
-
-
-
?
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
Q96KS0, Q9GZT9, Q9H6Z9
-
-
-
?
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
Q96KS0, Q9GZT9, Q9H6Z9
-
-
-
?
LAPYIPMDDDFQL + 2-oxoglutarate + O2
LA-((4R)-4-hydroxy-L-proline)-YIPMDDDFQL + succinate + CO2
show the reaction diagram
-, Q9GZT9, Q9H6Z9
Vmax is 90% of the activity with DLDLEMLAPYIPMDDDFQL
-
-
?
additional information
?
-
-, Q9GZT9, Q9H6Z9
the enzyme requires long peptide substrates. No hydroxylation of: Leu-Ala-Pro, Leu-Ala-Pro-Tyr, Leu-Glu-Met-Leu-Ala-Pro, and Leu-Glu-Met-Leu-Ala-Pro-Tyr
-
-
-
additional information
?
-
-
HIF prolyl-4-hydroxylase 2 substrate binding analysis using isolated sequences of the C-terminal oxygen degradation domain DLDLEALAP564YIPADDDFQL mutant M561A/M568A, and the N-terminal oxygen degradation domain DALTLLAP402AAGDTIISLDYG mutant F413Y, overview, substrate selectivity of PHD2 by kinetic competition assays, varied ionic strength, and global protein flexibility using amide H/D exchange, overview
-
-
-
additional information
?
-
Q96KS0, Q9GZT9, Q9H6Z9
the substrate contains a C-terminal and a N-terminal oxygen-dependent degradation domain, as well as a C-terminal transactivation domain
-
-
-
additional information
?
-
Q96KS0, Q9GZT9, Q9H6Z9
the subtrate contains a C-terminal and a N-terminal oxygen-dependent degradation domain, as well as a C-terminal transactivation domain
-
-
-
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
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-(4R)-4-hydroxy-L-proline + succinate + CO2
show the reaction diagram
-, Q9GZT9, Q9H6Z9
-
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-(4R)-4-hydroxy-L-proline + succinate + CO2
show the reaction diagram
-
HIF (hypoxia-inducible factor) is a transcription factor that plays a pivotal role in cellular adaptation to changes in oxygen availability. In the presence of oxygen, HIF is targeted for destruction by an E3 ubiquitin ligase containing the von Hippel-Lindau tumor suppressor protein (pVHL). Human pVHL binds to a short HIF-derived peptide when a conserved proline residue at the core of this peptide is hydroxylated. This protein modifiation may play a key role in mammalian oxygen sensing
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-(4R)-4-hydroxy-L-proline + succinate + CO2
show the reaction diagram
-
hypoxia-inducible factor (HIF) is a transcriptional complex that plays a central role in the regulation of gene expression by oxygen. In oxygenated and iron replete cells, HIF-alpha subunits are rapidly destroyed by a mechanism that involves ubiquitylation by the von Hippel-Lindau tumor suppressor (pVHL) E3 ligase complex. This process is suppressed by hypoxia and iron chelation, allowing transcriptional activation. The interaction between human pVHL and a specific domain of the HIF-1alpha subunit is regulated through hydroxylation of a proline residue (HIF-1alpha P564) by HIF-alpha prolyl-hydroxylase (HIF-PH). HIF-PH functions directly as a cellular oxygen sensor
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-(4R)-4-hydroxy-L-proline + succinate + CO2
show the reaction diagram
Q96KS0, Q9GZT9
mammalian cells respond to changes in oxygen availability through a conserved pathway that is regulated by the hypoxia-inducible factor (HIF). The alpha subunit of the hypoxia-inducible factor is targeted for degradation under normoxic conditions by a ubiquitin-ligase complex that recognizes a hydroxylated proline residue in hypoxia-inducible factor. HIF prolyl hydroxylase is responsible for this posttranslational modification
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-(4R)-4-hydroxy-L-proline + succinate + CO2
show the reaction diagram
Q96KS0, Q9GZT9
mammalian cells respond to changes in oxygen availability through a conserved pathway that is regulated by the hypoxia-inducible factor (HIF). The alpha subunit of the hypoxia-inducible factor is targeted for degradation under normoxic conditions by a ubiquitin-ligase complex that recognizes a hydroxylated proline residue in hypoxia-inducible factor. HIF prolyl is responsible for this posttranslational modification
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-trans-4-hydroxy-L-proline + succinate + CO2
show the reaction diagram
-
-
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-trans-4-hydroxy-L-proline + succinate + CO2
show the reaction diagram
Q96KS0, Q9GZT9, Q9H6Z9
-
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-trans-4-hydroxy-L-proline + succinate + CO2
show the reaction diagram
Q96KS0, Q9GZT9, Q9H6Z9
HIF1alpha is a better substrate than HIF2alpha for PHD2
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-trans-4-hydroxy-L-proline + succinate + CO2
show the reaction diagram
-
PHD enzymes hydroxylates HIF-alpha at prolyl residues present in the transcriptional activation domain N-TAD
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-trans-4-hydroxy-L-proline + succinate + CO2
show the reaction diagram
-
PHD2 hydroxylates Pro402 and/or Pro564 of HIF-1alpha
-
-
?
hypoxia-inducible factor-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-(3S)-3-hydroxy-proline + succinate + CO2
show the reaction diagram
-
HIF-1alpha
-
-
?
additional information
?
-
-
HIF prolyl-4-hydroxylase 2 substrate binding analysis using isolated sequences of the C-terminal oxygen degradation domain DLDLEALAP564YIPADDDFQL mutant M561A/M568A, and the N-terminal oxygen degradation domain DALTLLAP402AAGDTIISLDYG mutant F413Y, overview
-
-
-
METALS and IONS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
Fe2+
-
required. the enzyme activity is inhibited by substitution of Fe2+ with Co2+ or Ni2+
Fe2+
Q96KS0, Q9GZT9
the enzyme contains Fe2+; the enzyme contains Fe2+; the enzyme contains Fe2+
Fe2+
Q96KS0, Q9GZT9, Q9H6Z9
dependent on; dependent on; dependent on
Fe2+
-
required
Fe2+
-
dependent on, non-heme iron
Fe2+
-
dependent on
INHIBITORS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
1,1',1'',1'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetrapropan-2-ol
-
noncompetitive inhibition
1,1',1'',1'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetrapropan-2-ol
-
chelates Fe2+ in a hexacoordinative mode through four nitrogens of the macrocycle and two oxygens in side arms
2,2',2'',2'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetamide
-
chelates Fe2+ in a hexacoordinative mode through four nitrogens of the macrocycle and two oxygens in side arms
2,3-dihydroxypyridine
-
-
2-hydroxypyridine 1-oxide
-
-
-
3,3'-[(pyridin-2-ylmethyl)imino]dipropanenitrile
-
noncompetitive inhibition
3,3'-[(pyridin-4-ylimino)bis(propane-3,1-diyliminomethanediyl)]diphenol
-
noncompetitive inhibition
3,3'-[(pyridin-4-ylimino)bis[propane-3,1-diylnitrilo(Z)methylylidene]]diphenol
-
noncompetitive inhibition
3,6,9-tris(naphthalen-1-ylmethyl)-3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene
-
coordinates Fe2+ via triad or tetrad from nitrogen atoms of the parent ring, which leaves vacant position for other ligands binding
3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline
Q9GZT9, Q9H6Z9
-
3-cyano-6-methyl-2(H)-pyridinone
-
-
-
3-hydroxy-1,2-dimethyl-4(1H)-pyridinone
-
-
-
3-hydroxy-2-methyl-4-pyrone
-
-
-
3-hydroxypyridine-2-carbonyl-glycine
Q9GZT9, Q9H6Z9
-
4-Methylcatechol
-
-
4-nitrocatechol
-
-
4-tert-butylcatechol
-
-
5-hydroxy-2-hydroxymethyl-4-pyrone
-
-
-
5-hydroxy-4-oxo-4H-pyran-2-carboxylic acid
-
-
-
Cu2+
-
binding analysis
DLDLEALA-L-3,4-dehydroproline-YIPADDDFQLR
-
-
-
DLDLEALA-L-4-thioproline-YIPADDDFQLR
-
-
-
DLDLEALA-L-piperidine-2-carboxylic acid-YIPADDDFQLR
-
-
-
DLDLEALA-L-trans-4-fluoroproline-YIPADDDFQLR
-
-
-
DLDLEALA-L-trans-4-hydroxyproline-YIPADDDFQLR
-
-
-
H2O2
-
poor inhibition. Prolyl hydroxylase is less sensitive to peroxide, preferential inhibition of N803-hydroxylation by FIH, EC 1.14.11.30, compared with inhibition of P402/P564 hydroxylation by PHDs
N,N-dimethyl-5-[3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-trien-6-ylsulfonyl]naphthalen-1-amine
-
coordinates Fe2+ via triad or tetrad from nitrogen atoms of the parent ring, which leaves vacant position for other ligands binding
N-((3-hydroxy-6-chloroquinolin-2-yl)carbonyl)glycine
Q9GZT9, Q9H6Z9
-
N-(methoxyoxoacetyl)-glycine methyl ester
-
a pan-hydroxylase inhibitor, in vitro and in vivo inhibition
-
N-oxalyl-(2S)-alanine
-
competed by 2-oxoglutarate, no inhibition by the enantiomer N-oxalyl-(2R)-alanine
N-oxalylglycine
-
competed by 2-oxoglutarate
oxalylglycine
Q9GZT9, Q9H6Z9
-
oxygen
Q96KS0, Q9GZT9
the transiently overexpressed HPH-1 enzyme is inhibited by a low-oxygen environment
Pyridine-2,4-dicarboxylate
Q9GZT9, Q9H6Z9
-
JNJ1935
-
a prolyl-hydroxylase selective inhibitor. Low concentrations of JNJ1935 selectively inhibit PHDs, whereas higher concentrations inhibit all hydroxylases, including FIH, EC 1.14.11.30, in vitro and in vivo inhibition
-
additional information
-
the peptide inhibitors consist of amino acids identical to those in the CODD556-575 except the 564 proline residue, and target the C-terminal oxygen-dependent degradation domain binding site in the PHD2 active pocket. Specific inhibition of PHD2, no inhibition of FIH, EC 1.14.11.30
-
additional information
-
temporal dynamics of hydroxylase inhibition, overview
-
additional information
-
polynitrogen compound as HIF-1alpha PHD3 inhibitors, the metal complexes of these polynitrogen compounds cannot inhibit the catalytical activity of PHD3, overview. The inhibitory mechanism of PHD3 activity by polynitrogen compounds is due to their binding to iron to form stable coordination complexes
-
additional information
-
screening of iron chelators pyridines, hydroxypyrones/hydroxypyridinones, and catechols as inhibitors for PHD2, analysis of selectivity of the inhibitors for PHD2 compared to FIH, EC 1.14.11.30. Ligand binding kinetics and structural analysis, overview. Representative inhibitors bind to the metal center in PHD2 as an 2-oxoglutarate mimic
-
additional information
-
inhibition of the recombinant human PHD3 activity by tetraazamacrocycles, overview
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
ascorbate
Q9GZT9, Q9H6Z9
activates, Km: 0.14 mM; activates, Km: 0.17 mM; activates, Km: 0.18 mM
ascorbate
-
enhances activity
ascorbate
-
required
ascorbate
-
slightly activating
KM VALUE [mM]
KM VALUE [mM] Maximum
SUBSTRATE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.007
-
2-oxoglutarate
-
pH 7.0, 37C
0.055
-
2-oxoglutarate
Q9GZT9, Q9H6Z9
pH 7.8, 37C
0.06
-
2-oxoglutarate
Q9GZT9, Q9H6Z9
pH 7.8, 37C; pH 7.8, 37C
0.006
-
DALDLEMLAPYISMDDDFQL
Q9GZT9, Q9H6Z9
pH 7.8, 37C
0.007
-
DALDLEMLAPYISMDDDFQL
Q9GZT9, Q9H6Z9
pH 7.8, 37C
0.015
-
DALDLEMLAPYISMDDDFQL
Q9GZT9, Q9H6Z9
pH 7.8, 37C
0.13
-
DALTLLAPAAGDTIISLFG
Q9GZT9, Q9H6Z9
pH 7.8, 37C
0.38
-
DALTLLAPAAGDTIISLFG
Q9GZT9, Q9H6Z9
pH 7.8, 37C
0.01
-
DLDLEMLAPAIPMDDDFQL
Q9GZT9, Q9H6Z9
pH 7.8, 37C; pH 7.8, 37C
0.02
-
DLDLEMLAPAIPMDDDFQL
Q9GZT9, Q9H6Z9
pH 7.8, 37C
0.02
-
DLDLEMLAPGIPMDDDFQL
Q9GZT9, Q9H6Z9
pH 7.8, 37C; pH 7.8, 37C; pH 7.8, 37C
0.03
-
DLDLEMLAPYIPMD
Q9GZT9, Q9H6Z9
pH 7.8, 37C
0.1
-
DLDLEMLAPYIPMD
Q9GZT9, Q9H6Z9
pH 7.8, 37C; pH 7.8, 37C
0.009
-
DLDLEMLAPYIPMDD
Q9GZT9, Q9H6Z9
pH 7.8, 37C
0.06
-
DLDLEMLAPYIPMDD
Q9GZT9, Q9H6Z9
pH 7.8, 37C
0.1
-
DLDLEMLAPYIPMDD
Q9GZT9, Q9H6Z9
pH 7.8, 37C
0.007
-
DLDLEMLAPYIPMDDDF
Q9GZT9, Q9H6Z9
pH 7.8, 37C
0.05
-
DLDLEMLAPYIPMDDDF
Q9GZT9, Q9H6Z9
pH 7.8, 37C
0.07
-
DLDLEMLAPYIPMDDDF
Q9GZT9, Q9H6Z9
pH 7.8, 37C
0.007
-
DLDLEMLAPYIPMDDDFQL
Q9GZT9, Q9H6Z9
pH 7.8, 37C; pH 7.8, 37C
0.008
-
DLDLEMLAPYIPMDDDFQL
Q9GZT9, Q9H6Z9
pH 7.8, 37C
0.006
-
DLDLEMLAPYIPMDDDFQLRSFDQ
Q9GZT9, Q9H6Z9
pH 7.8, 37C; pH 7.8, 37C
0.008
-
DLDLEMLAPYIPMDDDFQLRSFDQ
Q9GZT9, Q9H6Z9
pH 7.8, 37C
0.007
-
DLEMLAPYIPMDDDFQL
Q9GZT9, Q9H6Z9
pH 7.8, 37C; pH 7.8, 37C
0.014
-
DLEMLAPYIPMDDDFQL
Q9GZT9, Q9H6Z9
pH 7.8, 37C
0.07
-
EEPDLSCLAPFVDTYDMMQM
Q9GZT9, Q9H6Z9
pH 7.8, 37C
0.1
-
EEPDLSCLAPFVDTYDMMQM
Q9GZT9, Q9H6Z9
pH 7.8, 37C
0.011
-
ELDLETLAPYIPMDGEDFQ
Q9GZT9, Q9H6Z9
pH 7.8, 37C
0.03
-
ELDLETLAPYIPMDGEDFQ
Q9GZT9, Q9H6Z9
pH 7.8, 37C; pH 7.8, 37C
0.05
-
EMLAPYIPMDD
Q9GZT9, Q9H6Z9
pH 7.8, 37C
0.007
-
EMLAPYIPMDDDFQL
Q9GZT9, Q9H6Z9
pH 7.8, 37C
0.035
-
EMLAPYIPMDDDFQL
Q9GZT9, Q9H6Z9
pH 7.8, 37C
0.08
-
EMLAPYIPMDDDFQL
Q9GZT9, Q9H6Z9
pH 7.8, 37C
0.06
-
EPEELAQLAPTPGDAIISLD
Q9GZT9, Q9H6Z9
pH 7.8, 37C
0.1
-
EPEELAQLAPTPGDAIISLD
Q9GZT9, Q9H6Z9
pH 7.8, 37C; pH 7.8, 37C
0.001
-
hypoxia-inducible factor-L-proline
-
C-terminal oxygen degradation domain DLDLEALAP564YIPADDDFQL mutant M561A/M568A in absence of NaCl, pH 7.0, 37C
0.0042
-
hypoxia-inducible factor-L-proline
-
C-terminal oxygen degradation domain DLDLEALAP564YIPADDDFQL mutant M561A/M568A in presence of 100 mM NaCl, pH 7.0, 37C
0.011
-
hypoxia-inducible factor-L-proline
-
N-terminal oxygen degradation domain DALTLLAP402AAGDTIISLDYG mutant F413Y in presence of 100 mM NaCl, pH 7.0, 37C
0.014
-
hypoxia-inducible factor-L-proline
-
N-terminal oxygen degradation domain DALTLLAP402AAGDTIISLDYG mutant F413Y in absence of NaCl, pH 7.0, 37C
0.067
-
hypoxia-inducible factor-L-proline
-
recombinant enzyme, pH 7.0, 37C
1.6e-05
-
hypoxia-inducible factor1alpha C-terminal oxygen-dependent degradation domain-L-proline
Q96KS0, Q9GZT9, Q9H6Z9
pH 7.5, 25C, PHD3
-
0.00075
0.00094
hypoxia-inducible factor1alpha C-terminal oxygen-dependent degradation domain-L-proline
Q96KS0, Q9GZT9, Q9H6Z9
pH 7.5, 25C, PHD2
-
0.0047
0.023
hypoxia-inducible factor2alpha C-terminal oxygen-dependent degradation domain-L-proline
Q96KS0, Q9GZT9, Q9H6Z9
pH 7.5, 25C, PHD3
-
0.23
-
O2
Q9GZT9, Q9H6Z9
pH 7.8, 37C; pH 7.8, 37C
0.25
-
O2
Q9GZT9, Q9H6Z9
pH 7.8, 37C
0.015
-
LAPYIPMDDDFQL
Q9GZT9, Q9H6Z9
pH 7.8, 37C
additional information
-
additional information
Q96KS0, Q9GZT9, Q9H6Z9
steady-state kinetic analysis and substrate selectivity for hypoxia-inducible factor and 2-oxoglutarate; steady-state kinetic analysis and substrate selectivity for hypoxia-inducible factor and 2-oxoglutarate; steady-state kinetic analysis and substrate selectivity for hypoxia-inducible factor and 2-oxoglutarate
-
additional information
-
additional information
-
kinetics, overview
-
TURNOVER NUMBER [1/s]
TURNOVER NUMBER MAXIMUM[1/s]
SUBSTRATE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.0101
-
hypoxia-inducible factor-L-proline
-
N-terminal oxygen degradation domain DALTLLAP402AAGDTIISLDYG mutant F413Y in absence of NaCl, pH 7.0, 37C
0.0103
-
hypoxia-inducible factor-L-proline
-
N-terminal oxygen degradation domain DALTLLAP402AAGDTIISLDYG mutant F413Y in presence of 100 mM NaCl, pH 7.0, 37C
0.0188
-
hypoxia-inducible factor-L-proline
-
C-terminal oxygen degradation domain DLDLEALAP564YIPADDDFQL mutant M561A/M568A in absence of NaCl, pH 7.0, 37C
0.02
-
hypoxia-inducible factor-L-proline
-
C-terminal oxygen degradation domain DLDLEALAP564YIPADDDFQL mutant M561A/M568A in presence of 100 mM NaCl, pH 7.0, 37C
0.0012
-
hypoxia-inducible factor1alpha C-terminal oxygen-dependent degradation domain-L-proline
Q96KS0, Q9GZT9, Q9H6Z9
pH 7.5, 25C, PHD3
-
0.0032
-
hypoxia-inducible factor1alpha C-terminal oxygen-dependent degradation domain-L-proline
Q96KS0, Q9GZT9, Q9H6Z9
pH 7.5, 25C, PHD2
-
0.0005
-
hypoxia-inducible factor2alpha C-terminal oxygen-dependent degradation domain-L-proline
Q96KS0, Q9GZT9, Q9H6Z9
pH 7.5, 25C, PHD3
-
kcat/KM VALUE [1/mMs-1]
kcat/KM VALUE [1/mMs-1] Maximum
SUBSTRATE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.72
-
hypoxia-inducible factor-L-proline
-
N-terminal oxygen degradation domain DALTLLAP402AAGDTIISLDYG mutant F413Y in absence of NaCl, pH 7.0, 37C
283711
0.94
-
hypoxia-inducible factor-L-proline
-
N-terminal oxygen degradation domain DALTLLAP402AAGDTIISLDYG mutant F413Y in presence of 100 mM NaCl, pH 7.0, 37C
283711
4.76
-
hypoxia-inducible factor-L-proline
-
C-terminal oxygen degradation domain DLDLEALAP564YIPADDDFQL mutant M561A/M568A in presence of 100 mM NaCl, pH 7.0, 37C
283711
18.8
-
hypoxia-inducible factor-L-proline
-
C-terminal oxygen degradation domain DLDLEALAP564YIPADDDFQL mutant M561A/M568A in absence of NaCl, pH 7.0, 37C
283711
Ki VALUE [mM]
Ki VALUE [mM] Maximum
INHIBITOR
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.00628
-
1,1',1'',1'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetrapropan-2-ol
-
recombinant enzyme, pH 7.0, 37C
0.067
-
1,1',1'',1'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetrapropan-2-ol
-
recombinant enzyme, pH 7.0, 37C
0.00998
-
2,2',2'',2'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetamide
-
recombinant enzyme, pH 7.0, 37C
0.0821
-
3,3'-[(pyridin-2-ylmethyl)imino]dipropanenitrile
-
recombinant enzyme, pH 7.0, 37C
0.0673
-
3,3'-[(pyridin-4-ylimino)bis(propane-3,1-diyliminomethanediyl)]diphenol
-
recombinant enzyme, pH 7.0, 37C
0.0253
-
3,3'-[(pyridin-4-ylimino)bis[propane-3,1-diylnitrilo(Z)methylylidene]]diphenol
-
recombinant enzyme, pH 7.0, 37C
0.00191
-
3,6,9-tris(naphthalen-1-ylmethyl)-3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene
-
recombinant enzyme, pH 7.0, 37C
0.01
-
3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline
Q9GZT9, Q9H6Z9
pH 7.8, 37C; pH 7.8, 37C
0.03
-
3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline
Q9GZT9, Q9H6Z9
pH 7.8, 37C
0.001
-
3-hydroxypyridine-2-carbonyl-glycine
Q9GZT9, Q9H6Z9
pH 7.8, 37C
0.002
-
3-hydroxypyridine-2-carbonyl-glycine
Q9GZT9, Q9H6Z9
pH 7.8, 37C
0.00249
-
N,N-dimethyl-5-[3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-trien-6-ylsulfonyl]naphthalen-1-amine
-
recombinant enzyme, pH 7.0, 37C
0.0002
-
N-((3-hydroxy-6-chloroquinolin-2-yl)carbonyl)glycine
Q9GZT9, Q9H6Z9
pH 7.8, 37C; pH 7.8, 37C
0.0008
-
N-((3-hydroxy-6-chloroquinolin-2-yl)carbonyl)glycine
Q9GZT9, Q9H6Z9
pH 7.8, 37C
0.008
-
oxalylglycine
Q9GZT9, Q9H6Z9
pH 7.8, 37C
0.01
-
oxalylglycine
Q9GZT9, Q9H6Z9
pH 7.8, 37C
0.05
-
oxalylglycine
Q9GZT9, Q9H6Z9
pH 7.8, 37C
0.007
-
Pyridine-2,4-dicarboxylate
Q9GZT9, Q9H6Z9
pH 7.8, 37C
0.008
-
Pyridine-2,4-dicarboxylate
Q9GZT9, Q9H6Z9
pH 7.8, 37C
0.04
-
Pyridine-2,4-dicarboxylate
Q9GZT9, Q9H6Z9
pH 7.8, 37C
0.015
-
3-hydroxypyridine-2-carbonyl-glycine
Q9GZT9, Q9H6Z9
pH 7.8, 37C
additional information
-
additional information
Q9GZT9, Q9H6Z9
Ki-values above 0.3 mM: pyridine-2,5-dicarboxylate and 3,4-dihydroxybenzoic acid; Ki-values above 0.3 mM: pyridine-2,5-dicarboxylate and 3,4-dihydroxybenzoic acid; Ki-values above 0.3 mM: pyridine-2,5-dicarboxylate and 3,4-dihydroxybenzoic acid
-
additional information
-
additional information
-
inhibition kinetics, overview
-
IC50 VALUE [mM]
IC50 VALUE [mM] Maximum
INHIBITOR
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.0295
-
1,1',1'',1'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetrapropan-2-ol
-
recombinant enzyme, pH 7.0, 37C
0.0397
-
1,1',1'',1'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetrapropan-2-ol
-
recombinant enzyme, pH 7.0, 37C
0.0309
-
2,2',2'',2'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetamide
-
recombinant enzyme, pH 7.0, 37C
0.005
-
2,3-dihydroxypyridine
-
pH 7.0, 37C
0.003
-
2-hydroxypyridine 1-oxide
-
pH 7.0, 37C
-
0.0604
-
3,3'-[(pyridin-2-ylmethyl)imino]dipropanenitrile
-
recombinant enzyme, pH 7.0, 37C
0.0128
-
3,3'-[(pyridin-4-ylimino)bis(propane-3,1-diyliminomethanediyl)]diphenol
-
recombinant enzyme, pH 7.0, 37C
0.016
-
3,3'-[(pyridin-4-ylimino)bis[propane-3,1-diylnitrilo(Z)methylylidene]]diphenol
-
recombinant enzyme, pH 7.0, 37C
0.0103
-
3,6,9-tris(naphthalen-1-ylmethyl)-3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene
-
recombinant enzyme, pH 7.0, 37C
1
-
3-cyano-6-methyl-2(H)-pyridinone
-
above, pH 7.0, 37C
-
0.04
-
3-hydroxy-1,2-dimethyl-4(1H)-pyridinone
-
pH 7.0, 37C
-
1
-
3-hydroxy-2-methyl-4-pyrone
-
above, pH 7.0, 37C
-
0.004
-
4-Methylcatechol
-
pH 7.0, 37C
0.006
-
4-nitrocatechol
-
pH 7.0, 37C
0.03
-
4-tert-butylcatechol
-
pH 7.0, 37C
0.4
-
5-hydroxy-2-hydroxymethyl-4-pyrone
-
pH 7.0, 37C
-
0.03
-
5-hydroxy-4-oxo-4H-pyran-2-carboxylic acid
-
pH 7.0, 37C
-
0.0207
-
N,N-dimethyl-5-[3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-trien-6-ylsulfonyl]naphthalen-1-amine
-
recombinant enzyme, pH 7.0, 37C
pH OPTIMUM
pH MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
7
-
-
assay at
7.5
-
Q96KS0, Q9GZT9, Q9H6Z9
assay at; assay at; assay at
7.8
-
Q9GZT9, Q9H6Z9
assay at; assay at; assay at
TEMPERATURE OPTIMUM
TEMPERATURE OPTIMUM MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
25
-
Q96KS0, Q9GZT9, Q9H6Z9
assay at; assay at; assay at
30
-
-
assay at
37
-
Q9GZT9, Q9H6Z9
assay at; assay at; assay at
37
-
-
assay at
SOURCE TISSUE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
SOURCE
Q9GZT9, Q9H6Z9
expression level of of HIF-P4H-3 mRNA is highest in the adult heart, brain, placenta, lung, and skeletal muscle and in the fetal heart, spleen, and skeletal muscle; the level of HIF-P4H-1 mRNA expression is highest in the adult brain, placenta, lung, and kidney; the levels of HIF-P4H-2 mRNA expression is highest in the adult heart, brain, lung, and liver and in the fetal brain, heart, spleen, and skeletal muscle
Manually annotated by BRENDA team
-
C-terminal domain and N-terminal domain of PDH2
Manually annotated by BRENDA team
Q9GZT9, Q9H6Z9
expression level of of HIF-P4H-3 mRNA is highest in the adult heart, brain, placenta, lung, and skeletal muscle and in the fetal heart, spleen, and skeletal muscle; the levels of HIF-P4H-2 mRNA expression is highest in the adult heart, brain, lung, and liver and in the fetal brain, heart, spleen, and skeletal muscle
Manually annotated by BRENDA team
Q9GZT9, Q9H6Z9
the level of HIF-P4H-1 mRNA expression is highest in the adult brain, placenta, lung, and kidney
Manually annotated by BRENDA team
Q9GZT9, Q9H6Z9
the levels of HIF-P4H-2 mRNA expression is highest in the adult heart, brain, lung, and liver and in the fetal brain, heart, spleen, and skeletal muscle
Manually annotated by BRENDA team
Q9GZT9, Q9H6Z9
expression level of of HIF-P4H-3 mRNA is highest in the adult heart, brain, placenta, lung, and skeletal muscle and in the fetal heart, spleen, and skeletal muscle; the level of HIF-P4H-1 mRNA expression is highest in the adult brain, placenta, lung, and kidney; the levels of HIF-P4H-2 mRNA expression is highest in the adult heart, brain, lung, and liver and in the fetal brain, heart, spleen, and skeletal muscle
Manually annotated by BRENDA team
Q9GZT9, Q9H6Z9
expression level of of HIF-P4H-3 mRNA is highest in the adult heart, brain, placenta, lung, and skeletal muscle and in the fetal heart, spleen, and skeletal muscle; the level of HIF-P4H-1 mRNA expression is highest in the adult brain, placenta, lung, and kidney
Manually annotated by BRENDA team
Q9GZT9, Q9H6Z9
expression level of of HIF-P4H-3 mRNA is highest in the adult heart, brain, placenta, lung, and skeletal muscle and in the fetal heart, spleen, and skeletal muscle; the levels of HIF-P4H-2 mRNA expression is highest in the adult heart, brain, lung, and liver and in the fetal brain, heart, spleen, and skeletal muscle
Manually annotated by BRENDA team
Q9GZT9, Q9H6Z9
expression level of of HIF-P4H-3 mRNA is highest in the adult heart, brain, placenta, lung, and skeletal muscle and in the fetal heart, spleen, and skeletal muscle; the levels of HIF-P4H-2 mRNA expression is highest in the adult heart, brain, lung, and liver and in the fetal brain, heart, spleen, and skeletal muscle
Manually annotated by BRENDA team
SUBUNITS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
?
-
x * 45642, recombinant N-terminally Trx- and C-terminally His-tagged enzyme, mass spectrometry, x * 45651, recombinant His-tagged enzyme, mass spectrometry, x * 45000, recombinant His-tagged enzyme, SDS-PAGE
Purification/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
-
Q96KS0, Q9GZT9
;
Q9GZT9, Q9H6Z9
recombinant GST-tagged PHD2 by glutathione affinity chromatography
-
recombinant His- and Strep-tagged tobacco etch virus-PHD1 from Escherichia coli strain BL21(DE3)pRR692 by nickel affinity and avidin affinity chromatography; recombinant His- and Strep-tagged tobacco etch virus-PHD2 from Escherichia coli strain BL21(DE3)pRR692 by nickel affinity and avidin affinity chromatography; recombinant N-terminally MBP-tagged PHD3 from Escherichia coli strain BL21(DE3)pRR692 by amylosse affinity chromatography
Q96KS0, Q9GZT9, Q9H6Z9
recombinant His-tagged enzyme from Escherichia coli strain BL21(DE3) by nickel affinity chromatography
-
recombinant N-terminally GST-tagged PHD2 residues 178-426 from Escherichia coli strain L21(DE3) by glutathione affinity chromatography
-
recombinant Trx- and His-tagged enzyme from Escherichia coli strain BL21(DE3)pLysS by nickel affinity chromatography to over 94% purity
-
Cloned/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
expression in Escherichia coli
Q96KS0, Q9GZT9
expression in Spodoptera frugiperda Sf9 cells and Escherichia coli; expression in Spodoptera frugiperda Sf9 cells and Escherichia coli; expression in Spodoptera frugiperda Sf9 cells and Escherichia coli
Q9GZT9, Q9H6Z9
expression of His-tagged human PHD3 in Escherichia coli strain BL21(DE3)
-
expression of N-terminally GST-tagged PHD2 residues 178-426 in Escherichia coli strain L21(DE3)
-
expression of N-terminally MBP-tagged PHD3 in Escherichia coli strain BL21(DE3)pRR692; expression of PHD1-(1-407) in Spodoptera frugiperda Sf9 cells using the baculovirus expression vector, expression of His- and Strep-tagged tobacco etch virus-PHD1 in Escherichia coli strain BL21(DE3)pRR692; expression of PHD2-(1-426) in Spodoptera frugiperda Sf9 cells uing the baculovirus expression vector, expression of His- and Strep-tagged tobacco etch virus-PHD2 in Escherichia coli strain BL21(DE3)pRR692
Q96KS0, Q9GZT9, Q9H6Z9
expression of PHD2 catalytic domain residues 177-426, expression of N-terminally GST-tagged PHD2 in Escherichia coli strain BL21(DE3)
-
recombinant expression of GST-tagged PHD2
-
the coding region of human PHD3 DNA is optimized by using synonymous codons according to the code bias of Escherichia coli, expression of soluble and active N-terminally Trx- and C-terminally His-tagged human PHD3 in Escherichia coli strain BL21(DE3)pLysS at lower induction temperature of 25C
-
ENGINEERING
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
D137A
Q96KS0, Q9GZT9
mutation eliminates prolyl hydroxylase activity of HPH-1
H135A
Q96KS0, Q9GZT9
mutation eliminates prolyl hydroxylase activity of HPH-1
H196A
Q96KS0, Q9GZT9
mutation eliminates prolyl hydroxylase activity of HPH-1
R367K
Q9GZT9, Q9H6Z9
inactive mutant of HIF-P4H-1
APPLICATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
drug development
-
the unique function of PHD2 makes it a prime target for selective inhibition leading to regulatory control of diseases such as cancer and stroke