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Information on EC 1.14.11.29 - hypoxia-inducible factor-proline dioxygenase and Organism(s) Mus musculus and UniProt Accession Q91UZ4

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IUBMB 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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Mus musculus
UNIPROT: Q91UZ4
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The taxonomic range for the selected organisms is: Mus musculus
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
Synonyms
egln1, prolyl hydroxylase domain, hph-1, egln2, hif prolyl, hif-ph, hif-prolyl hydroxylase, p4h-tm, prolyl hydroxylase-2, hif hydroxylase, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Hif-prolyl hydroxylase
-
prolyl 4-hydroxylase
-
HIF prolyl 4-hydroxylase
-
HIF-P4H-1
-
HIF-P4H-2
-
HIF-P4H-3
-
Hif-prolyl hydroxylase
-
PHD1
isoform
prolyl hydroxylase domain protein 2
-
prolyl-4-hydroxylase domain 2
-
-
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.
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
DLDLEMLAPYIPMDDDFQL + 2-oxoglutarate + O2
?
show the reaction diagram
-
-
-
?
hypoxia-inducible factor-alpha-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-alpha-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
-
-
-
?
DLDLEMLAPYIPMDDDFQL + 2-oxoglutarate + O2
?
show the reaction diagram
-
-
-
?
hypoxia-inducible factor 1 alpha-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor 1alpha-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
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
hypoxia-inducible factor-alpha-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor-alpha-trans-4-hydroxy-L-proline + succinate + CO2
show the reaction diagram
-
-
-
?
hypoxia-inducible factor 1 alpha-L-proline + 2-oxoglutarate + O2
hypoxia-inducible factor 1alpha-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
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Zn2+
the enzyme contains a zinc finger motif
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
6-[5-oxo-4-(1H-1,2,3-triazol-1-yl)-2,5-dihydro-1H-pyrazol-1-yl]pyridine-3-carboxylic acid
-
dimethyloxalylglycine
-
N-oxalylglycine
-
[(1-benzyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-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
-
[(4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonyl)amino]acetic acid
-
6-[5-oxo-4-(1H-1,2,3-triazol-1-yl)-2,5-dihydro-1H-pyrazol-1-yl]pyridine-3-carboxylic acid
-
dimethyloxalylglycine
-
N-oxalylglycine
-
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-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
-
[(4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbonyl)amino]acetic acid
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
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
Mus musculus
isoform PHD2, pH and temperature not specified in the publication
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
drug target
prolyl 4-hydroxylase domain protein 3 (PHD3) overexpression has therapeutic potential in treatment of obstructive sleep apnea and intermittent hypoxia induced cardiovascular fibrosis
evolution
the enzyme belongs to the HIF-PHD family of dioxygenases
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
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
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
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
physiological function
the HIF prolyl 4-hydroxylases (HIF-P4H) controls hypoxia-inducible factor (HIF), a powerful mechanism regulating cellular adaptation to decreased oxygenation. HIF-P4H-2 plays a major role in the regulation of hypoxic signalling in murine jejunum epithelium
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION?
EGLN3_MOUSE
239
0
27302
Swiss-Prot
other Location (Reliability: 3)
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
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
isozyme PHD3 is induced in cells in hypoxia in a HIF-dependent manner and plays a role in a negative-feedback loop
the expression of prolyl 4-hydroxylase domain protein 3 (PHD3) increases under hypoxia. Fibrosis improves when PHD3 is overexpressed
at 8 weeks of age the Hif-p4h isoforms 1, 2 and 3 are expressed in the jejunum epithelium at similar levels of 27, 35 and 29 copies/fg RNA. At 3 and 16 weeks of age, Hif-p4h-3 seems to have a slightly higher expression level than the other two isoforms. The caecum epithelium, Hif-p4h-2 has the highest abundance (109 copies/fg RNA input at 8 weeks of age) of the Hif-p4h isoforms, which is significantly higher when compared to Hif-p4h-3 (39 copies/fg RNA input). In the colon epithelium Hif-p4h-2 mRNA has the highest abundance (44 copies/fg RNA input) among the Hif-p4h isoforms, which is significantly higher than that of Hif-p4h-1 (18 copies/fg RNA input) and Fih1 (15 copies/fg RNA input), while the difference between the Hif-p4h-2 and Hif-p4h-3 (30 copies/fg RNA input) mRNA levels do not reach statistical significance
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
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
Manually annotated by BRENDA team
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)
Manually annotated by BRENDA team
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)
Manually annotated by BRENDA team
Taylor, C.T.; Scholz, C.C.
A PHD in macrophage survival
J. Leukoc. Biol.
96
365-375
2014
Mus musculus (Q91UZ4)
Manually annotated by BRENDA team
Tong, J.; Yu, F.C.; Li, Y.; Wei, Q.; Li, C.; Zhen, P.; Zhang, G.
Prolyl 4-hydroxylase domain protein 3-inhibited smooth-muscle-cell dedifferentiation improves cardiac perivascular fibrosis induced by obstructive sleep apnea
BioMed Res. Int.
2019
9174218
2019
Mus musculus (Q91UZ4)
Manually annotated by BRENDA team
Dengler, F.; Sova, S.; Salo, A.M.; Maeki, J.M.; Koivunen, P.; Myllyharju, J.
Expression and roles of individual HIF prolyl 4-hydroxylase isoenzymes in the regulation of the hypoxia response pathway along the murine gastrointestinal epithelium
Int. J. Mol. Sci.
22
4038
2021
Mus musculus (Q8BG58), Mus musculus
Manually annotated by BRENDA team