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Information on EC 1.14.11.29 - hypoxia-inducible factor-proline dioxygenase
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1.14.11.29 hypoxia-inducible factor-proline dioxygenaseIUBMB Comments
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.
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Word Map
- 1.14.11.29
- hydroxylases
- endothelial
-
angiogenesis
- erythropoietin
-
oxygen-dependent
- anemia
-
normoxic
- factor-1
-
hippel-lindau
-
altitude
- tetrahydrobiopterin
- erythrocytosis
-
oxygen-sensing
-
high-altitude
-
tibetan
- bh4
-
cyclohydrolase
-
highland
-
asparaginyl
-
2-oxoglutarate-dependent
-
eglns
-
hypoxia-responsive
- paragangliomas
- dmog
-
oxygen-sensitive
-
hifalpha
- polycythemia
-
hif-mediated
-
hif-independent
-
andeans
-
gtp-cyclohydrolase
-
hypoxia-sensing
-
hypoxia-related
- drug development
- pharmacology
- medicine
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
Reaction Schemes
Synonyms
egln1, prolyl hydroxylase domain, hph-1, egln2, hif prolyl, hif-prolyl hydroxylase, hif-ph, prolyl hydroxylase-2, hif hydroxylase, prolyl hydroxylase domain protein, 
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
EGLN1
EGLN3
HIF prolyl hydroxylase
Hif-prolyl hydroxylase
hydroxylase domain enzyme
PHD
PHD1
PHD2
PHD3
prolyl 4-hydroxylase
prolyl hydroxylase domain
prolyl-4-hydroxylase 2
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2 = hypoxia-inducible factor-trans-4-hydroxy-L-proline + succinate + CO2
-
-
-
-
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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.
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
DALDLEMLAPYISMDDDFQL + 2-oxoglutarate + O2
?
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
DALTLLAPAAGDTIISLFG + 2-oxoglutarate + O2
DALTLLA-((4R)-4-hydroxy-L-proline)-AAGDTIISLFG + succinate + CO2
DLDLEALAPYIPADDDFQL + 2-oxoglutarate + O2
hydroxylated DLDLEALA-((4R)-4-hydroxy-L-proline)-YIPADDDFQL+ succinate + CO2
-
-
?
DLDLEMLAPAIPMDDDFQL + 2-oxoglutarate + O2
DLDLEMLA-((4R)-4-hydroxy-L-proline)-AIPMDDDFQL + succinate + CO2
Vmax is 100% of the activity with DLDLEMLAPYIPMDDDFQL
-
?
DLDLEMLAPGIPMDDDFQL + 2-oxoglutarate + O2
DLDLEMLA-((4R)-4-hydroxy-L-proline)-GIPMDDDFQL + succinate + CO2
Vmax is 100% of the activity with DLDLEMLAPYIPMDDDFQL
-
?
DLDLEMLAPYIPMD + 2-oxoglutarate + O2
DLDLEMLA-((4R)-4-hydroxy-L-proline)-YIPMD + succinate + CO2
Vmax is 100% of the activity with DLDLEMLAPYIPMDDDFQL
-
?
DLDLEMLAPYIPMDD + 2-oxoglutarate + O2
DLDLEMLA-((4R)-4-hydroxy-L-proline)-YIPMDD + succinate + CO2
Vmax is 100% of the activity with DLDLEMLAPYIPMDDDFQL
-
?
DLDLEMLAPYIPMDDDF + 2-oxoglutarate + O2
DLDLEMLA-((4R)-4-hydroxy-L-proline)-YIPMDDDF + succinate + CO2
Vmax is 100% of the activity with DLDLEMLAPYIPMDDDFQL
-
?
DLDLEMLAPYIPMDDDFQL + 2-oxoglutarate + O2
DLDLEMLA-((4R)-4-hydroxy-L-proline)-YIPMDDDFQL + succinate + CO2
-
-
?
DLDLEMLAPYIPMDDDFQLRSFDQ + 2-oxoglutarate + O2
DLDLEMLA-((4R)-4-hydroxy-L-proline)-YIPMDDDFQLRSFDQ + succinate + CO2
Vmax is 100% of the activity with DLDLEMLAPYIPMDDDFQL
-
?
DLEMLAPYIPMDDDFQL + 2-oxoglutarate + O2
DLEMLA-((4R)-4-hydroxy-L-proline)-YIPMDDDFQL + succinate + CO2
Vmax is 100% of the activity with DLDLEMLAPYIPMDDDFQL
-
?
ELDLETLAPYIPMDGEDFQ + 2-oxoglutarate + O2
ELDLETLA-((4R)-4-hydroxy-L-proline)-YIPMDGEDFQ + succinate + CO2
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
Vmax is 30% of the activity with DLDLEMLAPYIPMDDDFQL
-
?
EMLAPYIPMDDDFQL + 2-oxoglutarate + O2
EMLA-((4R)-4-hydroxy-L-proline)-YIPMDDDFQL + succinate + CO2
hypoxia-inducible factor 1 alpha-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor 1alpha-trans-4-hydroxy-L-proline + succinate + CO2
-
-
?
hypoxia-inducible factor 1alpha-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor 1alpha-trans-4-hydroxy-L-proline + succinate + CO2
-
-
-
?
hypoxia-inducible factor-alpha-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-alpha-trans-4-hydroxy-L-proline + succinate + CO2
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-(4R)-4-hydroxy-L-proline + succinate + CO2
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-trans-4-hydroxy-L-proline + succinate + CO2
hypoxia-inducible factor-L-proline peptide + 2-oxoglutarate + O2
hypoxia-inducible factor-trans-4-hydroxy-L-proline peptide + succinate + CO2
-
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
-
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
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
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
-
-
?
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
-
-
?
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
-
-
?
LAPYIPMDDDFQL + 2-oxoglutarate + O2
LA-((4R)-4-hydroxy-L-proline)-YIPMDDDFQL + succinate + CO2
Vmax is 90% of the activity with DLDLEMLAPYIPMDDDFQL
-
?
DALDLEMLAPYISMDDDFQL + 2-oxoglutarate + O2
DALDLEMLA-((4R)-4-hydroxy-L-proline)-YISMDDDFQL + succinate + CO2
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
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
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
N-terminal hydroxylation site of HIF-1alpha, Vmax is 60% of the activity with DLDLEMLAPYIPMDDDFQL
-
?
EEPDLSCLAPFVDTYDMMQM + 2-oxoglutarate + O2
?
hydroxylation site of Caenorhabditis elegans HIF-alpha. Vmax is 60% of the activity with DLDLEMLAPYIPMDDDFQL
-
?
EEPDLSCLAPFVDTYDMMQM + 2-oxoglutarate + O2
?
hydroxylation site of Caenorhabditis elegans HIF-alpha. Vmax is 80% of the activity with DLDLEMLAPYIPMDDDFQL
-
?
ELDLETLAPYIPMDGEDFQ + 2-oxoglutarate + O2
?
C-terminal hydroxylation site of HIF-2alpha. Vmax is 100% of the activity with DLDLEMLAPYIPMDDDFQL
-
?
ELDLETLAPYIPMDGEDFQ + 2-oxoglutarate + O2
?
C-terminal hydroxylation site of HIF-2alpha. Vmax is 70% of the activity with DLDLEMLAPYIPMDDDFQL
-
?
EMLAPYIPMDDDFQL + 2-oxoglutarate + O2
EMLA-((4R)-4-hydroxy-L-proline)-YIPMDDDFQL + succinate + CO2
Vmax is 100% of the activity with DLDLEMLAPYIPMDDDFQL
-
?
EMLAPYIPMDDDFQL + 2-oxoglutarate + O2
EMLA-((4R)-4-hydroxy-L-proline)-YIPMDDDFQL + succinate + CO2
Vmax is 80% of the activity with DLDLEMLAPYIPMDDDFQL
-
?
EPEELAQLAPTPGDAIISLD + 2-oxoglutarate + O2
?
N-terminal hydroxylation site of HIF-2alpha. Vmax is 30% of the activity with DLDLEMLAPYIPMDDDFQL
-
?
EPEELAQLAPTPGDAIISLD + 2-oxoglutarate + O2
?
N-terminal hydroxylation site of HIF-2alpha. Vmax is 70% of the activity with DLDLEMLAPYIPMDDDFQL
-
?
EPEELAQLAPTPGDAIISLD + 2-oxoglutarate + O2
?
N-terminal hydroxylation site of HIF-2alpha. Vmax is 80% of the activity with DLDLEMLAPYIPMDDDFQL
-
?
hypoxia-inducible factor-alpha-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-alpha-trans-4-hydroxy-L-proline + succinate + CO2
-
-
?
hypoxia-inducible factor-alpha-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-alpha-trans-4-hydroxy-L-proline + succinate + CO2
-
-
-
?
hypoxia-inducible factor-alpha-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-alpha-trans-4-hydroxy-L-proline + succinate + CO2
-
-
?
hypoxia-inducible factor-alpha-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-alpha-trans-4-hydroxy-L-proline + succinate + CO2
-
-
?
hypoxia-inducible factor-alpha-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-alpha-trans-4-hydroxy-L-proline + succinate + CO2
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-(4R)-4-hydroxy-L-proline + succinate + CO2
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-(4R)-4-hydroxy-L-proline + succinate + CO2
-
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-(4R)-4-hydroxy-L-proline + succinate + CO2
-
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
-
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
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
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
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
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
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
-
hypoxia-inducible factor 1alpha is hydroxylated at Pro402 and Pro564
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-trans-4-hydroxy-L-proline + succinate + CO2
-
hypoxia-inducible factor 1alpha is hydroxylated at Pro402 and Pro564
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-trans-4-hydroxy-L-proline + succinate + CO2
-
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-trans-4-hydroxy-L-proline + succinate + CO2
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-trans-4-hydroxy-L-proline + succinate + CO2
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-trans-4-hydroxy-L-proline + succinate + CO2
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-trans-4-hydroxy-L-proline + succinate + CO2
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-trans-4-hydroxy-L-proline + succinate + CO2
-
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-trans-4-hydroxy-L-proline + succinate + CO2
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
-
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
-
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
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
-
hydroxylation at P402 and P564
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-trans-4-hydroxy-L-proline + succinate + CO2
-
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
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
the PHD1 reaction at the N-terminal oxygen-dependent degradation domain site shows low level hydroxylation
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-trans-4-hydroxy-L-proline + succinate + CO2
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-trans-4-hydroxy-L-proline + succinate + CO2
-
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-trans-4-hydroxy-L-proline + succinate + CO2
-
-
?
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
-
-
?
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
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
-
-
?
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
low activity
-
?
additional information
?
-
-
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
?
-
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
?
-
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
-
?
additional information
?
-
-
substrate selectivity of PHD2 by kinetic competition assays, varied ionic strength, and global protein flexibility using amide H/D exchange, overview
-
?
additional information
?
-
the substrate contains a C-terminal and a N-terminal oxygen-dependent degradation domain, as well as a C-terminal transactivation domain
-
?
additional information
?
-
the substrate contains a C-terminal and a N-terminal oxygen-dependent degradation domain, as well as a C-terminal transactivation domain
-
?
additional information
?
-
the substrate contains a C-terminal and a N-terminal oxygen-dependent degradation domain, as well as a C-terminal transactivation domain
-
?
additional information
?
-
the subtrate contains a C-terminal and a N-terminal oxygen-dependent degradation domain, as well as a C-terminal transactivation domain
-
?
additional information
?
-
the subtrate contains a C-terminal and a N-terminal oxygen-dependent degradation domain, as well as a C-terminal transactivation domain
-
?
additional information
?
-
the subtrate contains a C-terminal and a N-terminal oxygen-dependent degradation domain, as well as a C-terminal transactivation domain
-
?
additional information
?
-
-
isozyme PHD2 is more active on hypoxia-inducible factor-1alpha than on hypoxia-inducible factor-2alpha, whereas PHD1 and PHD3 hydroxylate hypoxia-inducible factor-2alpha more efficiently
-
?
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
hypoxia-inducible factor 1 alpha-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor 1alpha-trans-4-hydroxy-L-proline + succinate + CO2
-
-
-
?
hypoxia-inducible factor 1alpha-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor 1alpha-trans-4-hydroxy-L-proline + succinate + CO2
-
-
-
-
?
hypoxia-inducible factor-alpha-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-alpha-trans-4-hydroxy-L-proline + succinate + CO2
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-(4R)-4-hydroxy-L-proline + succinate + CO2
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-trans-4-hydroxy-L-proline + succinate + CO2
hypoxia-inducible factor-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-(3S)-3-hydroxy-proline + succinate + CO2
-
HIF-1alpha
-
-
?
hypoxia-inducible factor-alpha-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-alpha-trans-4-hydroxy-L-proline + succinate + CO2
-
-
-
?
hypoxia-inducible factor-alpha-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-alpha-trans-4-hydroxy-L-proline + succinate + CO2
-
-
-
-
?
hypoxia-inducible factor-alpha-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-alpha-trans-4-hydroxy-L-proline + succinate + CO2
-
-
-
?
hypoxia-inducible factor-alpha-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-alpha-trans-4-hydroxy-L-proline + succinate + CO2
-
-
-
?
hypoxia-inducible factor-alpha-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-alpha-trans-4-hydroxy-L-proline + succinate + CO2
-
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-(4R)-4-hydroxy-L-proline + succinate + CO2
-
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-(4R)-4-hydroxy-L-proline + succinate + CO2
-
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
-
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
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
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
-
hypoxia-inducible factor 1alpha is hydroxylated at Pro402 and Pro564
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-trans-4-hydroxy-L-proline + succinate + CO2
-
hypoxia-inducible factor 1alpha is hydroxylated at Pro402 and Pro564
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-trans-4-hydroxy-L-proline + succinate + CO2
-
-
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-trans-4-hydroxy-L-proline + succinate + CO2
-
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-trans-4-hydroxy-L-proline + succinate + CO2
-
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-trans-4-hydroxy-L-proline + succinate + CO2
-
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-trans-4-hydroxy-L-proline + succinate + CO2
-
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-trans-4-hydroxy-L-proline + succinate + CO2
-
-
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-trans-4-hydroxy-L-proline + succinate + CO2
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
-
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
-
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
-
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-trans-4-hydroxy-L-proline + succinate + CO2
-
-
-
-
?
hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-trans-4-hydroxy-L-proline + succinate + CO2
-
-
-
?
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
-
-
?
additional information
?
-
-
isozyme PHD2 is more active on hypoxia-inducible factor-1alpha than on hypoxia-inducible factor-2alpha, whereas PHD1 and PHD3 hydroxylate hypoxia-inducible factor-2alpha more efficiently
-
-
?
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Fe2+
Fe2+
-
required. the enzyme activity is inhibited by substitution of Fe2+ with Co2+ or Ni2+
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(2R)-[2-[2-(5-cyano-3-hydroxypyridin-2-yl)-1,3-thiazol-4-yl]acetamido](phenyl)acetic acid
-
-
(2S)-[2-[2-(5-cyano-3-hydroxypyridin-2-yl)-1,3-thiazol-4-yl]acetamido](phenyl)acetic acid
-
-
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-(2-(5-cyano-3-hydroxy-4-methylpyridin-2-yl)-5-methylthiazol-4-yl)-N-(2-(diethylamino)ethyl)acetamide
-
-
2-(2-(5-cyano-3-hydroxy-4-methylpyridin-2-yl)-5-phenylthiazol-4-yl)-N-(2-(pyridin-2-yl)ethyl)acetamide
-
-
2-(2-(5-cyano-3-hydroxypyridin-2-yl)-5-phenylthiazol-4-yl)-N-(2-(pyridin-2-yl)ethyl)acetamide
-
-
2-[2-(5-cyano-3-hydroxy-4-methylpyridin-2-yl)-1,3-thiazol-4-yl]-N-[2-(diethylamino)ethyl]acetamide
-
-
2-[2-(5-cyano-3-hydroxy-4-methylpyridin-2-yl)-1,3-thiazol-4-yl]-N-[2-(pyridin-2-yl)ethyl]acetamide
-
-
2-[2-(5-cyano-3-hydroxy-4-methylpyridin-2-yl)-5-methyl-1,3-thiazol-4-yl]-N-propylacetamide
-
-
2-[2-(5-cyano-3-hydroxy-4-methylpyridin-2-yl)-5-methyl-1,3-thiazol-4-yl]-N-[2-(pyridin-2-yl)ethyl]acetamide
-
-
2-[2-(5-cyano-3-hydroxypyridin-2-yl)-1,3-thiazol-4-yl]-N-(2-phenylethyl)acetamide
-
-
2-[2-(5-cyano-3-hydroxypyridin-2-yl)-1,3-thiazol-4-yl]-N-[(1R)-2-hydroxy-1-phenylethyl]acetamide
-
-
2-[2-(5-cyano-3-hydroxypyridin-2-yl)-1,3-thiazol-4-yl]-N-[(1S)-2-hydroxy-1-phenylethyl]acetamide
-
-
2-[2-(5-cyano-3-hydroxypyridin-2-yl)-1,3-thiazol-4-yl]-N-[2-(pyridin-2-yl)ethyl]acetamide
-
-
2-[2-(5-cyano-3-hydroxypyridin-2-yl)-5-methyl-1,3-thiazol-4-yl]-N-[2-(pyridin-2-yl)ethyl]acetamide
-
-
2-[2-[2-(5-cyano-3-hydroxypyridin-2-yl)-1,3-thiazol-4-yl]acetamido]-2-methylpropanoic acid
-
-
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
5-hydroxy-6-[4-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-1,3-thiazol-2-yl]pyridine-3-carbonitrile
-
-
7-[(4-chlorophenyl)[(3-hydroxypyridin-2-yl)amino]methyl]quinolin-8-ol
-
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
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
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-((3,4-dimethoxyphenyl)(8-hydroxyquinolin-7-yl)methyl)-2-phenylacetamide
-
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
oxygen
the transiently overexpressed HPH-1 enzyme is inhibited by a low-oxygen environment
[(2E)-3-hydroxy-2-({[(naphthalen-2-yl)methanesulfonyl]acetyl}imino)-2,3-dihydro-1,3-thiazol-4-yl]acetic acid
[2-(5-cyano-3-hydroxypyridin-2-yl)-6-oxo-1,6-dihydropyrimidin-5-yl]acetic acid
-
-
[2-[2-(5-cyano-3-hydroxypyridin-2-yl)-1,3-thiazol-4-yl]acetamido]acetic acid
-
-
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
6-[5-oxo-4-(1H-1,2,3-triazol-1-yl)-2,5-dihydro-1H-pyrazol-1-yl]pyridine-3-carboxylic acid
-
6-[5-oxo-4-(1H-1,2,3-triazol-1-yl)-2,5-dihydro-1H-pyrazol-1-yl]pyridine-3-carboxylic acid
-
tert-butyl 6-(5-oxo-4-(1H-1,2,3-triazol-1-yl)-2,5-dihydro-1H-pyrazol-1-yl)nicotinate
potent and selective inhibitor of isoform PHD2
tert-butyl 6-(5-oxo-4-(1H-1,2,3-triazol-1-yl)-2,5-dihydro-1H-pyrazol-1-yl)nicotinate
potent and selective inhibitor of isoform PHD2
[(1-benzyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonyl)amino]acetic acid
-
[(1-benzyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonyl)amino]acetic acid
-
[(1-chloro-4-hydroxyisoquinoline-3-carbonyl)amino]acetic acid
-
[(1-chloro-4-hydroxyisoquinoline-3-carbonyl)amino]acetic acid
-
[(2E)-3-hydroxy-2-({[(naphthalen-2-yl)methanesulfonyl]acetyl}imino)-2,3-dihydro-1,3-thiazol-4-yl]acetic acid
-
[(2E)-3-hydroxy-2-({[(naphthalen-2-yl)methanesulfonyl]acetyl}imino)-2,3-dihydro-1,3-thiazol-4-yl]acetic acid
-
[(4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonyl)amino]acetic acid
-
[(4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonyl)amino]acetic acid
-
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
-
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.000016 - 0.00094
hypoxia-inducible factor1alpha C-terminal oxygen-dependent degradation domain-L-proline
-
0.0047 - 0.023
hypoxia-inducible factor2alpha C-terminal oxygen-dependent degradation domain-L-proline
pH 7.5, 25°C, PHD3
-
0.001
hypoxia-inducible factor-L-proline
-
C-terminal oxygen degradation domain DLDLEALAP564YIPADDDFQL mutant M561A/M568A in absence of NaCl, pH 7.0, 37°C
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, 37°C
0.011
hypoxia-inducible factor-L-proline
-
N-terminal oxygen degradation domain DALTLLAP402AAGDTIISLDYG mutant F413Y in presence of 100 mM NaCl, pH 7.0, 37°C
0.014
hypoxia-inducible factor-L-proline
-
N-terminal oxygen degradation domain DALTLLAP402AAGDTIISLDYG mutant F413Y in absence of NaCl, pH 7.0, 37°C
0.000016
hypoxia-inducible factor1alpha C-terminal oxygen-dependent degradation domain-L-proline
pH 7.5, 25°C, PHD3
-
0.00075 - 0.00094
hypoxia-inducible factor1alpha C-terminal oxygen-dependent degradation domain-L-proline
pH 7.5, 25°C, PHD2
-
additional information
additional information
steady-state kinetic analysis and substrate selectivity for hypoxia-inducible factor and 2-oxoglutarate
-
additional information
additional information
steady-state kinetic analysis and substrate selectivity for hypoxia-inducible factor and 2-oxoglutarate
-
additional information
additional information
steady-state kinetic analysis and substrate selectivity for hypoxia-inducible factor and 2-oxoglutarate
-
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0012 - 0.0032
hypoxia-inducible factor1alpha C-terminal oxygen-dependent degradation domain-L-proline
-
0.0005
hypoxia-inducible factor2alpha C-terminal oxygen-dependent degradation domain-L-proline
pH 7.5, 25°C, PHD3
-
0.0101
hypoxia-inducible factor-L-proline
-
N-terminal oxygen degradation domain DALTLLAP402AAGDTIISLDYG mutant F413Y in absence of NaCl, pH 7.0, 37°C
0.0103
hypoxia-inducible factor-L-proline
-
N-terminal oxygen degradation domain DALTLLAP402AAGDTIISLDYG mutant F413Y in presence of 100 mM NaCl, pH 7.0, 37°C
0.0188
hypoxia-inducible factor-L-proline
-
C-terminal oxygen degradation domain DLDLEALAP564YIPADDDFQL mutant M561A/M568A in absence of NaCl, pH 7.0, 37°C
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, 37°C
0.0012
hypoxia-inducible factor1alpha C-terminal oxygen-dependent degradation domain-L-proline
pH 7.5, 25°C, PHD3
-
0.0032
hypoxia-inducible factor1alpha C-terminal oxygen-dependent degradation domain-L-proline
pH 7.5, 25°C, PHD2
-
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
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, 37°C
0.94
hypoxia-inducible factor-L-proline
-
N-terminal oxygen degradation domain DALTLLAP402AAGDTIISLDYG mutant F413Y in presence of 100 mM NaCl, pH 7.0, 37°C
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, 37°C
18.8
hypoxia-inducible factor-L-proline
-
C-terminal oxygen degradation domain DLDLEALAP564YIPADDDFQL mutant M561A/M568A in absence of NaCl, pH 7.0, 37°C
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.00628 - 0.067
1,1',1'',1'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetrapropan-2-ol
0.00998
2,2',2'',2'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetamide
-
recombinant enzyme, pH 7.0, 37°C
0.0821
3,3'-[(pyridin-2-ylmethyl)imino]dipropanenitrile
-
recombinant enzyme, pH 7.0, 37°C
0.0673
3,3'-[(pyridin-4-ylimino)bis(propane-3,1-diyliminomethanediyl)]diphenol
-
recombinant enzyme, pH 7.0, 37°C
0.0253
3,3'-[(pyridin-4-ylimino)bis[propane-3,1-diylnitrilo(Z)methylylidene]]diphenol
-
recombinant enzyme, pH 7.0, 37°C
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, 37°C
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, 37°C
0.00628
1,1',1'',1'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetrapropan-2-ol
-
recombinant enzyme, pH 7.0, 37°C
0.067
1,1',1'',1'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetrapropan-2-ol
-
recombinant enzyme, pH 7.0, 37°C
0.0002
N-((3-hydroxy-6-chloroquinolin-2-yl)carbonyl)glycine
pH 7.8, 37°C
0.0008
N-((3-hydroxy-6-chloroquinolin-2-yl)carbonyl)glycine
pH 7.8, 37°C
additional information
additional information
-
Ki-values above 0.3 mM: pyridine-2,5-dicarboxylate and 3,4-dihydroxybenzoic acid
-
additional information
additional information
Ki-values above 0.3 mM: pyridine-2,5-dicarboxylate and 3,4-dihydroxybenzoic acid
-
additional information
additional information
Ki-values above 0.3 mM: pyridine-2,5-dicarboxylate and 3,4-dihydroxybenzoic acid
-
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0026
(2R)-[2-[2-(5-cyano-3-hydroxypyridin-2-yl)-1,3-thiazol-4-yl]acetamido](phenyl)acetic acid
Homo sapiens
-
pH and temperature not specified in the publication
0.0028
(2S)-[2-[2-(5-cyano-3-hydroxypyridin-2-yl)-1,3-thiazol-4-yl]acetamido](phenyl)acetic acid
Homo sapiens
-
pH and temperature not specified in the publication
0.0295 - 0.0397
1,1',1'',1'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetrapropan-2-ol
0.0309
2,2',2'',2'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetamide
Homo sapiens
-
recombinant enzyme, pH 7.0, 37°C
0.0004
2-(2-(5-cyano-3-hydroxy-4-methylpyridin-2-yl)-5-methylthiazol-4-yl)-N-(2-(diethylamino)ethyl)acetamide
Homo sapiens
-
pH and temperature not specified in the publication
0.0057
2-(2-(5-cyano-3-hydroxy-4-methylpyridin-2-yl)-5-phenylthiazol-4-yl)-N-(2-(pyridin-2-yl)ethyl)acetamide
Homo sapiens
-
pH and temperature not specified in the publication
0.024
2-(2-(5-cyano-3-hydroxypyridin-2-yl)-5-phenylthiazol-4-yl)-N-(2-(pyridin-2-yl)ethyl)acetamide
Homo sapiens
-
pH and temperature not specified in the publication
0.0038
2-[2-(5-cyano-3-hydroxy-4-methylpyridin-2-yl)-1,3-thiazol-4-yl]-N-[2-(diethylamino)ethyl]acetamide
Homo sapiens
-
pH and temperature not specified in the publication
0.0007
2-[2-(5-cyano-3-hydroxy-4-methylpyridin-2-yl)-1,3-thiazol-4-yl]-N-[2-(pyridin-2-yl)ethyl]acetamide
Homo sapiens
-
pH and temperature not specified in the publication
0.0014
2-[2-(5-cyano-3-hydroxy-4-methylpyridin-2-yl)-5-methyl-1,3-thiazol-4-yl]-N-propylacetamide
Homo sapiens
-
pH and temperature not specified in the publication
0.0008
2-[2-(5-cyano-3-hydroxy-4-methylpyridin-2-yl)-5-methyl-1,3-thiazol-4-yl]-N-[2-(pyridin-2-yl)ethyl]acetamide
Homo sapiens
-
pH and temperature not specified in the publication
0.0034
2-[2-(5-cyano-3-hydroxypyridin-2-yl)-1,3-thiazol-4-yl]-N-(2-phenylethyl)acetamide
Homo sapiens
-
pH and temperature not specified in the publication
0.0021
2-[2-(5-cyano-3-hydroxypyridin-2-yl)-1,3-thiazol-4-yl]-N-[(1R)-2-hydroxy-1-phenylethyl]acetamide
Homo sapiens
-
pH and temperature not specified in the publication
0.0024
2-[2-(5-cyano-3-hydroxypyridin-2-yl)-1,3-thiazol-4-yl]-N-[(1S)-2-hydroxy-1-phenylethyl]acetamide
Homo sapiens
-
pH and temperature not specified in the publication
0.003
2-[2-(5-cyano-3-hydroxypyridin-2-yl)-1,3-thiazol-4-yl]-N-[2-(pyridin-2-yl)ethyl]acetamide
Homo sapiens
-
pH and temperature not specified in the publication
0.0012
2-[2-(5-cyano-3-hydroxypyridin-2-yl)-5-methyl-1,3-thiazol-4-yl]-N-[2-(pyridin-2-yl)ethyl]acetamide
Homo sapiens
-
pH and temperature not specified in the publication
0.0073
2-[2-[2-(5-cyano-3-hydroxypyridin-2-yl)-1,3-thiazol-4-yl]acetamido]-2-methylpropanoic acid
Homo sapiens
-
pH and temperature not specified in the publication
0.0604
3,3'-[(pyridin-2-ylmethyl)imino]dipropanenitrile
Homo sapiens
-
recombinant enzyme, pH 7.0, 37°C
0.0128
3,3'-[(pyridin-4-ylimino)bis(propane-3,1-diyliminomethanediyl)]diphenol
Homo sapiens
-
recombinant enzyme, pH 7.0, 37°C
0.016
3,3'-[(pyridin-4-ylimino)bis[propane-3,1-diylnitrilo(Z)methylylidene]]diphenol
Homo sapiens
-
recombinant enzyme, pH 7.0, 37°C
0.0103
3,6,9-tris(naphthalen-1-ylmethyl)-3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene
Homo sapiens
-
recombinant enzyme, pH 7.0, 37°C
0.002
5-hydroxy-6-[4-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-1,3-thiazol-2-yl]pyridine-3-carbonitrile
Homo sapiens
-
pH and temperature not specified in the publication
0.0000048
6-[5-oxo-4-(1H-1,2,3-triazol-1-yl)-2,5-dihydro-1H-pyrazol-1-yl]pyridine-3-carboxylic acid
Homo sapiens
isoform PHD2, pH and temperature not specified in the publication
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
Homo sapiens
-
recombinant enzyme, pH 7.0, 37°C
0.081
N-benzyl-2-[2-(3-hydroxypyridin-2-yl)-1,3-thiazol-4-yl]acetamide
Homo sapiens
-
pH and temperature not specified in the publication
0.0054
N-benzyl-2-[2-(5-cyano-3-hydroxypyridin-2-yl)-1,3-thiazol-4-yl]acetamide
Homo sapiens
-
pH and temperature not specified in the publication
0.0000016
tert-butyl 6-(5-oxo-4-(1H-1,2,3-triazol-1-yl)-2,5-dihydro-1H-pyrazol-1-yl)nicotinate
0.000022
[(1-benzyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonyl)amino]acetic acid
Homo sapiens
isoform PHD2, pH and temperature not specified in the publication
0.195
[2-(3-hydroxypyridin-2-yl)-1,3-thiazol-4-yl]acetic acid
Homo sapiens
-
pH and temperature not specified in the publication
0.0275
[2-(3-hydroxypyridin-2-yl)-6-oxo-1,6-dihydropyrimidin-5-yl]acetic acid
Homo sapiens
-
pH and temperature not specified in the publication
0.006
[2-(5-cyano-3-hydroxypyridin-2-yl)-1,3-thiazol-4-yl]acetic acid
Homo sapiens
-
pH and temperature not specified in the publication
0.0135
[2-(5-cyano-3-hydroxypyridin-2-yl)-6-oxo-1,6-dihydropyrimidin-5-yl]acetic acid
Homo sapiens
-
pH and temperature not specified in the publication
0.0022
[2-[2-(5-cyano-3-hydroxypyridin-2-yl)-1,3-thiazol-4-yl]acetamido]acetic acid
Homo sapiens
-
pH and temperature not specified in the publication
0.0295
1,1',1'',1'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetrapropan-2-ol
Homo sapiens
-
recombinant enzyme, pH 7.0, 37°C
0.0397
1,1',1'',1'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetrapropan-2-ol
Homo sapiens
-
recombinant enzyme, pH 7.0, 37°C
0.0000022
N-oxalylglycine
Homo sapiens
isoform PHD2, pH and temperature not specified in the publication
0.0000022
N-oxalylglycine
Mus musculus
isoform PHD2, pH and temperature not specified in the publication
0.0000016
tert-butyl 6-(5-oxo-4-(1H-1,2,3-triazol-1-yl)-2,5-dihydro-1H-pyrazol-1-yl)nicotinate
Homo sapiens
isoform PHD2, pH and temperature not specified in the publication
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
-
-
brenda
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
detected only in the initial stages of embryo development
brenda
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
brenda
the level of HIF-P4H-1 mRNA expression is highest in the adult brain, placenta, lung, and kidney
brenda
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
brenda
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
brenda
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
brenda
the level of HIF-P4H-1 mRNA expression is highest in the adult brain, placenta, lung, and kidney
brenda
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
brenda
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
brenda
the level of HIF-P4H-1 mRNA expression is highest in the adult brain, placenta, lung, and kidney
brenda
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
brenda
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
brenda
the level of HIF-P4H-1 mRNA expression is highest in the adult brain, placenta, lung, and kidney
brenda
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
brenda
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
brenda
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
brenda
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
brenda
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
malfunction
metabolism
physiological function
additional information
evolution
the enzyme belongs to the of the 2-oxoglutarate- and iron-dependent dioxygenase family of enzymes
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
malfunction
-
hypoxia-inducible factor prolyl hydroxylase 2 knockdown leads to a less sustained activation of epidermal growth factor receptor and its downstream signaling pathways
malfunction
-
inactivation of Phd2 in endothelial cells specifically results in severe pulmonary hypertension but not polycythemia and is associated with abnormal muscularization of peripheral pulmonary arteries and right ventricular hypertrophy
malfunction
isoform PHD3 silencing leads to downregulation of most glycolytic enzymes from glucose transport to lactate production supported by the reduction in extracellular acidification and lactate production and increase in cellular oxygen consumption rate
malfunction
macrophages deficient in PHD3 have decreased levels of stress-induced apoptosis. The antiapoptotic effects of PHD3 knockout are independent of alterations in HIF and instead, appear to occur via reduced expression of Angptl2, an extracellular protein that is structurally similar to angiopoietins. Hypoxia-dependent PHD3 inhibition in macrophages promotes cell survival through the activation of HIF-dependent adaptive pathways and HIF-independent antiapoptotic pathways, including decreased expression of Angptl2, impact of altered PHD3 expression/activity on macrophage function, schematic overview
malfunction
PHD2 knockdown causes a marked reduction of erythropoietin (EPO) production. HIF seems not to be involved in this process
malfunction
the gene expression of p50 is reduced in the PHD2 knockdown cells, while the protein amount and the subcellular distribution of p65 are not changed in the PHD2 knockdown cells. The transactivation activity of NFkappaB is consequently decreased in the PHD2 knockdown cells. The expression levels of HIF target genes GLUT1 and VEGF-A is significantly upregulated in the PHD2 knockdown cells. The gene expression of BNIP3 is decreased. The influence of PHD2 knockdown on the gene expression of HIF-1alpha, HIF-2alpha, and p50 is not caused by off-target effect
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
metabolism
-
optimal HIF-1alpha transcriptional activity requires sequential inhibition of both prolyl- and asparaginyl-hydroxylases
metabolism
-
isoforms PHD2 and 3 inhibit IkappaB kinase and decrease the activity of the nuclear factor-kappaB pathway. Isoform PHD2 also acts as a negative regulator of nuclear factor-kappaB during arteriogenesis
metabolism
-
isoforms PHD2 and 3 inhibit IkappaB kinase and decrease the activityof the nuclear factor-kappaB pathway. Isoform PHD2 also acts as a negative regulator of nuclear factor-kappaB during arteriogenesis
metabolism
PDH2 regulates hypoxia-inducible factor (HIF)-independent pathways, as well as the degradation pathway of HIFalpha. HIF-2alpha does not play a major role in the regulation of erythropoietin (EPO) expression by PHD2
metabolism
PHD isoforms have a differential contribution in controlling hypoxia-inducible factor (HIF)-alpha degradation and activity
metabolism
PHD isoforms have a differential contribution in controlling hypoxia-inducible factor (HIF)-alpha degradation and activity
metabolism
PHD isoforms have a differential contribution in controlling hypoxia-inducible factor (HIF)-alpha degradation and activity. Hydroxylases are key oxygen sensors expressed in all cells that regulate the adaptive response to hypoxia and promote a return to oxygen homeostasis. Complex crosstalk exists between inflammatory and hypoxic signaling pathways
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
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
physiological function
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
-
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
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
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
physiological function
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
-
hypoxia-inducible factor prolyl hydroxylase 2 is a direct regulator of epidermal growth factor receptor signaling in breast cancer
physiological function
isoform PHD3 is involved in the maintenance of key cellular functions including glycolysis and protein synthesis in clear cell renal cell carcinoma. The enzyme regulates ribosomal subunits and protein translation in clear cell renal cell carcinoma
physiological function
isoform PHD3 plays important roles in hypoxia response and early embryo development of Megalobrama amblycephala
physiological function
enzyme PHD2 is to mediate the oxygen-dependent degradation of the labile alpha-subunit of hypoxia-inducible factor (HIF). In the erythropoietin (EPO)-producing human HCC cell line HepG2, PHD2 maintains the expression of hepatocyte nuclear factor-4alpha (HNF-4alpha), an important mediator of EPO expression in hepatocytes, by inhibiting the auto-/paracrine signalling of transforming growth factor-beta1. PHD2 also regulates HIF-independent pathways by interacting with other substrates. In HepG2 cells, PHD2 suppresses the activity of TGF-beta1 pathway and consequently maintains the expression of hepatocyte nuclear factor-4alpha (HNF-4alpha), an important transcription factor promoting the erythropoietin (EPO) expression in hepatocytes. PHD2 represents a potential contributing factor for hepatocellular carcinoma-associated erythrocytosis. Erythrocytosis generally leads to elevated blood viscosity and is a significant risk factor for lung artery thromboembolism, a life-threatening condition. The ability of some HCC cells to secrete EPO, a glycoprotein hormone which promotes erythropoiesis, contributes to HCC-associated erythrocytosis
physiological function
oxygen deprivation (hypoxia) is a common feature of solid tumors in advanced stages. The primary cellular transcriptional responses to hypoxia are mainly mediated by the transcription factor hypoxia-inducible factor (HIF). HIF consists of an oxygen-labile alpha-subunit (HIF-1alpha, HIF-2alpha) and a stable beta-subunit (ARNT). Prolyl-4-hydroxylase 2 (PHD2) is an important mediator of the oxygen-dependent degradation of HIF-alpha subunits. Prolyl-4-hydroxylase 2 enhances hypoxia-induced glioblastoma cell death by regulating the gene expression of hypoxia-inducible factor-alpha. In the glioblastoma cells, PHD2 maintains the gene expression of HIF-1alpha in dependence of nuclear factor kappaB and suppresses the gene expression of HIF-2alpha through HIF-1alpha. The PHD2-mediated degradation of HIF-1alpha and HIF-2alpha seems less important. PHD2 maintains the gene expression of the NFkappaB subunit p50 in glioblastoma cells. PHD2 enhances hypoxia-induced glioblastoma cell death by modulating the expression of the HIF target genes glucose transporter 1, vascular endothelial growth factor-A and Bcl-2 binding protein 3. PHD2 inhibits the adaptation of glioblastoma cells to hypoxia by regulating the HIF-alpha subunits in a non-canonical way. But exogenous PHD2 has no impact on the gene expression of HIF-1alpha and HIF-2alpha in glioblastoma cells
physiological function
PHD2 controls the expression of many of the pro-catabolic and inflammatory genes that are known to be involved with the degenerative cascade and matrix breakdown. Prolyl-4-hydroxylase domain protein 2 controls NF-kappaB/p65 transactivation and enhances the catabolic effects of inflammatory cytokines on cells of the nucleus pulposus, regulatory mechanism of PHD2 function and expression under inflammatory conditions in the nucleus pulposus, overview. PHD2 controls TNF-alpha effects by positively regulating NF-kappaB signaling, whereas NF-kappaB mediates cytokine-dependent PHD2 expression. PHD2 and NF-kappaB form a functional circuit that promotes the catabolic effects of TNF-alpha in the intervertebral disc. PHD2 is a potent regulator of the catabolic activities of TNF-alpha, silencing of PHD2 significantly decreases TNF-alpha-induced expression of catabolic markers including SDC4, MMP-3, MMP-13, and ADAMTS5, as well as several inflammatory cytokines and chemokines, while partially restoring aggrecan and collagen II expression
physiological function
PHD2 controls the expression of many of the pro-catabolic and inflammatory genes that are known to be involved with the degenerative cascade and matrix breakdown. Prolyl-4-hydroxylase domain protein 2 controls NF-kappaB/p65 transactivation and enhances the catabolic effects of inflammatory cytokines on cells of the nucleus pulposus, regulatory mechanism of PHD2 function and expression under inflammatory conditions in the nucleus pulposus, overview. PHD2 controls TNF-alpha effects by positively regulating NF-kappaB signaling, whereas NF-kappaB mediates cytokine-dependent PHD2 expression. PHD2 and NF-kappaB form a functional circuit that promotes the catabolic effects of TNF-alpha in the intervertebral disc. PHD2 is a potent regulator of the catabolic activities of TNF-alpha, silencing of PHD2 significantly decreases TNF-alpha-induced expression of catabolic markers including SDC4, MMP-3, MMP-13, and ADAMTS5, as well as several inflammatory cytokines and chemokines, while partially restoring aggrecan and collagen II expression
physiological function
the HIF-PHDs (PHD1, PHD2, and PHD3, also known as EGLN2, EGLN1, and EGLN3, respectively) are a family of dioxygenases that use non-mitochondrial molecular oxygen as a cosubstrate in the hydroxylation of two residues, in what is termed the oxygen-dependent degradation domain of the HIFalpha isoform (Pro402 and Pro564 on HIF-1alpha). Hydroxylation of oxygen-dependent degradation domain of the HIFalpha isoform residues Pro402 and Pro564 renders the HIFalpha subunit as a target for the von Hipple Lindau protein, which recruits an E3 ubiquitin ligase complex that ubiquitinates HIF, leading to its proteasomal degradation. This process is prevented in hypoxia, leading to the rapid stabilization of HIFalpha, which is then free to translocate to the nucleus, to bind to HIF1beta/aryl hydrocarbon receptor nuclear translocator, and to form the transcriptionally active HIF complex. Isozyme PHD3 is proposed to play a role in a negative-feedback loop, curtailing the HIF-dependent response in prolonged hypoxia, presumably, to prevent excessive angiogenesis and other adaptive processes
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
additional information
-
PHD has a higher affinity for oxygen than FIH, EC 1.14.11.30
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UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). EGLN1_HUMAN
426
0
46021
Swiss-Prot
other Location (Reliability: 2)
EGLN1_MOUSE
400
0
43111
Swiss-Prot
other Location (Reliability: 1)
EGLN1_RAT
338
0
36093
Swiss-Prot
Mitochondrion (Reliability: 5)
EGLN2_HUMAN
407
0
43650
Swiss-Prot
other Location (Reliability: 1)
EGLN2_MOUSE
419
0
45109
Swiss-Prot
other Location (Reliability: 2)
EGLN2_RAT
415
0
44681
Swiss-Prot
other Location (Reliability: 2)
EGLN3_HUMAN
239
0
27261
Swiss-Prot
other Location (Reliability: 3)
EGLN3_MOUSE
239
0
27302
Swiss-Prot
other Location (Reliability: 3)
EGLN3_RAT
239
0
27242
Swiss-Prot
other Location (Reliability: 3)
P4HTM_HUMAN
502
1
56661
Swiss-Prot
other Location (Reliability: 4)
P4HTM_MOUSE
503
1
57049
Swiss-Prot
other Location (Reliability: 3)
EGL9_CAEEL
723
0
79743
Swiss-Prot
other Location (Reliability: 1)
A0A061IBH8_CRIGR
126
0
14425
TrEMBL
other Location (Reliability: 2)
A0A061HTK4_CRIGR
390
0
41860
TrEMBL
other Location (Reliability: 2)
A0A061IAF3_CRIGR
148
0
17076
TrEMBL
other Location (Reliability: 1)
A0A061IG52_CRIGR
140
0
15833
TrEMBL
other Location (Reliability: 2)
A0A061IDG7_CRIGR
127
0
14320
TrEMBL
other Location (Reliability: 2)
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PDB
SCOP
CATH
UNIPROT
ORGANISM
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MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
45000
-
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
45642
-
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
45651
-
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
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SUBUNIT
ORGANISM
UNIPROT
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
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CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
isoform PHD2 in complex with Mn2+, sitting drop vapor diffusion method, using 1.6 M sodium citrate/citric acid pH 6.5
isoform PHD2 in complex with Mn2+, sitting drop vapor diffusion method, using 1.6 M sodium citrate/citric acid pH 6.5
isoform PHD2 in complex with Mn2+, sitting drop vapor diffusion method, using 1.6 M sodium citrate/citric acid pH 6.5
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
D315E
substitution of the Fe(II)-binding aspartate for a glutamate residue manifests significantly reduced Fe(II) binding, yet maintains catalytic activity with a 5fold faster reaction with O2
R383K
disruption of 2OG binding in this variant does not accelerate O2 activation
T387A
the mutant shows 15fold increased turnover at limiting O2 concentrations compared to the wild type enzyme
T387N
the mutant shows about 2fold reduced turnover at limiting O2 concentrations compared to the wild type enzyme
additional information
additional information
siRNA against PHD2 causes sufficient PHD2 knockdown in glioblastoma cell lines U-87MG, U-138MG, and U-343MG
additional information
the expression of PHD2 gene is silenced via specific siRNA (siPHD2) in the erythropoietin (EPO)-producing human HCC cell line HepG2. PHD2 knockdown causes a marked reduction of erythropoietin (EPO) production. HIF seems not to be involved in this process
additional information
-
the expression of PHD2 gene is silenced via specific siRNA (siPHD2) in the erythropoietin (EPO)-producing human HCC cell line HepG2. PHD2 knockdown causes a marked reduction of erythropoietin (EPO) production. HIF seems not to be involved in this process
additional information
PDH2 knockout in NP cells lentiviral expression of shPHD2, phenotype, overview. TNF-alpha-dependent induction in expression of PHD3, SDC4, MMP13, and ADAMTS5, catabolic marker genes that are hallmark of disc degeneration, is significantly reduced in PHD2 silenced cells. Silencing of PHD2 significantly restores the TNF-alpha-mediated reduction in aggrecan sand collagen II
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PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
GSTrap column chromatography and Hitrap benzamidine column 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 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 N-terminally MBP-tagged PHD3 from Escherichia coli strain BL21(DE3)pRR692 by amylosse affinity chromatography
recombinant Trx- and His-tagged enzyme from Escherichia coli strain BL21(DE3)pLysS by nickel affinity chromatography to over 94% purity
-
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expression in Spodoptera frugiperda Sf9 cells and Escherichia coli
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 catalytic domain residues 177-426, expression of N-terminally GST-tagged PHD2 in Escherichia coli strain BL21(DE3)
-
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
gene EGLN1
gene EGLN1, recombinant expression in HEK 293T cells from vector pRL-TK containing Renilla reniformis luciferase gene, real-time RT-PCR enzyme expression analysis
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 25°C
-
gene EGLN1, recombinant expression in HEK 293T cells from vector pRL-TK containing Renilla reniformis luciferase gene, real-time RT-PCR enzyme expression analysis
gene EGLN1, recombinant expression in HEK 293T cells from vector pRL-TK containing Renilla reniformis luciferase gene, real-time RT-PCR enzyme expression analysis
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
after hypoxia treatment the enzyme expression is significantly increased in all analyzed tissues
isozyme PHD3 is induced in cells in hypoxia in a HIF-dependent manner and plays a role in a negative-feedback loop
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APPLICATION
ORGANISM
UNIPROT
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
medicine
pharmacology
modulation of PHD2 activity might be considered as a new way to inhibit glioblastoma progression
medicine
during disc degeneration PHD2 may offer a therapeutic target to mitigate the deleterious actions of TNF-alpha, a key proinflammatory cytokine
medicine
PHD2 represents a potential contributing factor for hepatocellular carcinoma-associated erythrocytosis. Selective inhibition of PHD2 in HCC cells might be considered as a way to manage erythrocytosis in hepatocellular carcinoma (HCC) patients
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Hirsila, M.; Koivunen, P.; Gunzler, V.; Kivirikko, K.I.; Myllyharju, J.
Characterization of the human prolyl 4-hydroxylases that modify the hypoxia-inducible factor
J. Biol. Chem.
278
30772-30780
2003
Homo sapiens, Homo sapiens (Q9GZT9), Homo sapiens (Q9H6Z9)
brenda
Ivan, M.; Kondo, K.; Yang, H.F.; Kim, W.; Valiando, J.; Ohh, M.; Salic, A.; Asara, J.M.; Lane, W.S.; Kaelin, W.G.
HIF alpha targeted for VHL-mediated destruction by proline hydroxylation: Implications for O2 sensing
Science
292
464-468
2001
Homo sapiens
brenda
Jaakkola, P.; Mole, D.R.; Tian, Y.M.; Wilson, M.I.; Gielbert, J.; Gaskell, S.J.; von Kriegsheim, A.; Hebestreit, H.F.; Mukherji, M.; Schofield, C.J.; Maxwell, P.H.; Pugh, C.W.; Ratcliffe, P.J.
Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation
Science
292
468-472
2001
Homo sapiens
brenda
Bruick, R.K.; McKnight, S.L.
A conserved family of prolyl-4-hydroxylases that modify HIF
Science
294
1337-1340
2001
Drosophila melanogaster, Homo sapiens, Homo sapiens (Q96KS0), Homo sapiens (Q9GZT9)
brenda
Pappalardi, M.B.; McNulty, D.E.; Martin, J.D.; Fisher, K.E.; Jiang, Y.; Burns, M.C.; Zhao, H.; Ho, T.; Sweitzer, S.; Schwartz, B.; Annan, R.S.; Copeland, R.A.; Tummino, P.J.; Luo, L.
Biochemical characterization of human HIF hydroxylases using HIF protein substrates that contain all three hydroxylation sites
Biochem. J.
436
363-369
2011
Homo sapiens (Q96KS0), Homo sapiens (Q9GZT9), Homo sapiens (Q9H6Z9)
brenda
Kwon, H.S.; Choi, Y.K.; Kim, J.W.; Park, Y.K.; Yang, E.G.; Ahn, D.R.
Inhibition of a prolyl hydroxylase domain (PHD) by substrate analog peptides
Bioorg. Med. Chem. Lett.
21
4325-4328
2011
Homo sapiens
brenda
Cavadas, M.A.; Nguyen, L.K.; Cheong, A.
Hypoxia-inducible factor (HIF) network: insights from mathematical models
Cell Commun. Signal.
11
42
2013
Homo sapiens
brenda
Masson, N.; Singleton, R.S.; Sekirnik, R.; Trudgian, D.C.; Ambrose, L.J.; Miranda, M.X.; Tian, Y.M.; Kessler, B.M.; Schofield, C.J.; Ratcliffe, P.J.
The FIH hydroxylase is a cellular peroxide sensor that modulates HIF transcriptional activity
EMBO Rep.
13
251-257
2012
Homo sapiens
brenda
Nguyen, L.K.; Cavadas, M.A.; Scholz, C.C.; Fitzpatrick, S.F.; Bruning, U.; Cummins, E.P.; Tambuwala, M.M.; Manresa, M.C.; Kholodenko, B.N.; Taylor, C.T.; Cheong, A.
A dynamic model of the hypoxia-inducible factor 1alpha (HIF-1alpha) network
J. Cell Sci.
126
1454-1463
2013
Homo sapiens
brenda
Geng, Z.; Zhu, J.; Cao, J.; Geng, J.; Song, X.; Zhang, Z.; Bian, N.; Wang, Z.
Effects of polynitrogen compounds on the activity of recombinant human HIF-1alpha prolyl hydroxylase 3 in E. coli
J. Inorg. Biochem.
105
391-399
2011
Homo sapiens
brenda
Flagg, S.C.; Martin, C.B.; Taabazuing, C.Y.; Holmes, B.E.; Knapp, M.J.
Screening chelating inhibitors of HIF-prolyl hydroxylase domain 2 (PHD2) and factor inhibiting HIF (FIH)
J. Inorg. Biochem.
113
25-30
2012
Homo sapiens
brenda
Pektas, S.; Knapp, M.J.
Substrate preference of the HIF-prolyl hydroxylase-2 (PHD2) and substrate-induced conformational change
J. Inorg. Biochem.
126
55-60
2013
Homo sapiens
brenda
Cao, J.; Geng, Z.; Ma, X.; Wen, J.; Yin, Y.; Wang, Z.
Evidence for inhibition of HIF-1alpha prolyl hydroxylase 3 activity by four biologically active tetraazamacrocycles
Org. Biomol. Chem.
10
3913-3923
2012
Homo sapiens
brenda
Chen, N.; Huang, C.H.; Chen, B.X.; Liu, H.; Wang, W.M.; Gul, Y.; Wang, H.L.
Alternative splicing transcription of Megalobrama amblycephala HIF prolyl hydroxylase PHD3 and up-regulation of PHD3 by HIF-1alpha
Biochem. Biophys. Res. Commun.
469
737-742
2016
Megalobrama amblycephala (A0A140EDB6)
brenda
Tarhonskaya, H.; Chowdhury, R.; Leung, I.K.; Loik, N.D.; McCullagh, J.S.; Claridge, T.D.; Schofield, C.J.; Flashman, E.
Investigating the contribution of the active site environment to the slow reaction of hypoxia-inducible factor prolyl hydroxylase domain 2 with oxygen
Biochem. J.
463
363-372
2014
Homo sapiens (Q9GZT9), Homo sapiens
brenda
Pektas, S.; Taabazuing, C.Y.; Knapp, M.J.
Increased turnover at limiting O2 concentrations by the Thr387 -> Ala variant of HIF-prolyl hydroxylase PHD2
Biochemistry
54
2851-2857
2015
Homo sapiens (Q9GZT9), Homo sapiens
brenda
Osipyants, A.; Smirnova, N.; Khristichenko, A.; Hushpulian, D.; Nikulin, S.; Chubar, T.; Zakhariants, A.; Tishkov, V.; Gazaryan, I.; Poloznikov, A.
Enzyme–substrate reporters for evaluation of substrate specificity of HIF prolyl hydroxylase isoforms
Biochemistry
82
1207-1214
2017
Homo sapiens (Q96KS0), Homo sapiens (Q9GZT9), Homo sapiens (Q9H6Z9)
brenda
Fan, L.; Li, J.; Yu, Z.; Dang, X.; Wang, K.
The hypoxia-inducible factor pathway, prolyl hydroxylase domain protein inhibitors, and their roles in bone repair and regeneration
BioMed Res. Int.
2014
239356
2014
Homo sapiens
brenda
Hong, Y.R.; Kim, H.T.; Ro, S.; Cho, J.M.; Lee, S.H.; Kim, I.S.; Jung, Y.H.
Discovery of novel 2-[2-(3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetamide derivatives as HIF prolyl 4-hydroxylase inhibitors; SAR, synthesis and modeling evaluation
Bioorg. Med. Chem. Lett.
24
3142-3145
2014
Homo sapiens
brenda
Miikkulainen, P.; Hoegel, H.; Rantanen, K.; Suomi, T.; Kouvonen, P.; Elo, L.L.; Jaakkola, P.M.
HIF prolyl hydroxylase PHD3 regulates translational machinery and glucose metabolism in clear cell renal cell carcinoma
Cancer Metab.
5
5-5
2017
Homo sapiens (Q9H6Z9)
brenda
Bishop, T.; Ratcliffe, P.J.
HIF hydroxylase pathways in cardiovascular physiology and medicine
Circ. Res.
117
65-79
2015
Homo sapiens
brenda
Badawi, Y.; Shi, H.
Relative contribution of prolyl hydroxylase-dependent and -independent degradation of HIF-1alpha by proteasomal pathways in cerebral ischemia
Front. Neurosci.
11
239
2017
Homo sapiens
brenda
Wang, L.; Cui, S.; Ma, L.; Kong, L.; Geng, X.
Current advances in the novel functions of hypoxia-inducible factor and prolyl hydroxylase in invertebrates
Insect Mol. Biol.
24
634-648
2015
Caenorhabditis elegans, Drosophila melanogaster
brenda
Giannetto, A.; Maisano, M.; Cappello, T.; Oliva, S.; Parrino, V.; Natalotto, A.; De Marco, G.; Barberi, C.; Romeo, O.; Mauceri, A.; Fasulo, S.
Hypoxia-inducible factor alpha and Hif-prolyl hydroxylase characterization and gene expression in short-time air-exposed Mytilus galloprovincialis
Mar. Biotechnol.
17
768-781
2015
Mytilus galloprovincialis (A0A0K0M9M3), Mytilus galloprovincialis
brenda
Kapitsinou, P.P.; Rajendran, G.; Astleford, L.; Michael, M.; Schonfeld, M.P.; Fields, T.; Shay, S.; French, J.L.; West, J.; Haase, V.H.
The endothelial prolyl-4-hydroxylase domain 2/hypoxia-inducible factor 2 axis regulates pulmonary artery pressure in mice
Mol. Cell. Biol.
36
1584-1594
2016
Mus musculus
brenda
Arsenault, P.R.; Song, D.; Chung, Y.J.; Khurana, T.S.; Lee, F.S.
The zinc finger of prolyl hydroxylase domain protein 2 is essential for efficient hydroxylation of hypoxia-inducible factor alpha
Mol. Cell. Biol.
36
2328-2343
2016
Mus musculus (Q91YE2)
brenda
Kozlova, N.; Wottawa, M.; Katschinski, D.M.; Kristiansen, G.; Kietzmann, T.
Hypoxia-inducible factor prolyl hydroxylase 2 (PHD2) is a direct regulator of epidermal growth factor receptor (EGFR) signaling in breast cancer
Oncotarget
8
9885-9898
2017
Homo sapiens
brenda
Chan, M.C.; Atasoylu, O.; Hodson, E.; Tumber, A.; Leung, I.K.; Chowdhury, R.; Gomez-Perez, V.; Demetriades, M.; Rydzik, A.M.; Holt-Martyn, J.; Tian, Y.M.; Bishop, T.; Claridge, T.D.; Kawamura, A.; Pugh, C.W.; Ratcliffe, P.J.; Schofield, C.J.
Potent and selective triazole-based inhibitors of the hypoxia-inducible factor prolyl-hydroxylases with activity in the murine brain
PLoS ONE
10
e0132004
2015
Mus musculus (Q91UZ4), Mus musculus (Q91YE2), Mus musculus (Q91YE3), Homo sapiens (Q96KS0), Homo sapiens (Q9GZT9), Homo sapiens (Q9H6Z9)
brenda
Sun, W.; Jelkmann, W.; Depping, R.
Prolyl-4-hydroxylase 2 enhances hypoxia-induced glioblastoma cell death by regulating the gene expression of hypoxia-inducible factor-alpha
Cell Death Dis.
5
e1322
2014
Homo sapiens (Q9GZT9)
brenda
Sun, W.; Kosyna, F.K.; Jelkmann, W.; Depping, R.
Prolyl-4-hydroxylase 2 potentially contributes to hepatocellular carcinoma-associated erythrocytosis by maintaining hepatocyte nuclear factor-4alpha expression
Cell. Physiol. Biochem.
37
2257-2264
2015
Homo sapiens (Q9GZT9), Homo sapiens
brenda
Li, J.; Yuan, W.; Jiang, S.; Ye, W.; Yang, H.; Shapiro, I.M.; Risbud, M.V.
Prolyl-4-hydroxylase domain protein 2 controls NF-kappaB/p65 transactivation and enhances the catabolic effects of inflammatory cytokines on cells of the nucleus pulposus
J. Biol. Chem.
290
7195-7207
2015
Rattus norvegicus (P59722), Homo sapiens (Q9GZT9)
brenda
Taylor, C.T.; Scholz, C.C.
A PHD in macrophage survival
J. Leukoc. Biol.
96
365-375
2014
Mus musculus (Q91UZ4)
brenda
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