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Information on EC 1.14.11.2 - procollagen-proline 4-dioxygenase and Organism(s) Mus musculus and UniProt Accession Q6W3F0
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1.14.11.2 procollagen-proline 4-dioxygenaseIUBMB Comments
Requires Fe2+ and ascorbate.The enzyme, which is located within the lumen of the endoplasmic reticulum, catalyses the 4-hydroxylation of prolines in -X-Pro-Gly- sequences. The 4-hydroxyproline residues are essential for the formation of the collagen triple helix. The enzyme forms a complex with protein disulfide isomerase and acts not only on procollagen but also on more than 15 other proteins that have collagen-like domains.
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Word Map
- 1.14.11.2
- anemia
- fibrosis
- procollagens
- endothelial
- erythropoietin
- hydroxylases
- tetramer
- hemoglobin
-
lysyl
- beta-subunits
-
oxygen-dependent
- 4-hydroxyproline
- ascorbate
-
roxadustat
-
normoxia
- hippel-lindau
- alpha-subunits
-
erythropoiesis-stimulating
- hepcidin
-
myofibroblasts
- dmog
-
hif-alpha
-
oxygen-sensing
-
glucosyltransferase
-
fibroblast-like
-
alpha-smooth
-
hif-prolyl
- erythrocytosis
-
triple-helical
-
collagen-like
-
hif-dependent
-
4-hydroxylation
-
alpha2beta2
-
treatment-emergent
-
alphai
-
hypoxia-responsive
- 3,4-dihydroxybenzoate
-
3-hydroxylase
-
2-oxoglutarate-dependent
-
hippel
- dimethyloxalylglycine
-
darbepoetin
-
non-dialysis-dependent
-
asparaginyl
- medicine
-
hif-mediated
- diagnostics
- analysis
- nutrition
- drug development
The taxonomic range for the selected organisms is: Mus musculus
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Reaction Schemes
Synonyms
prolyl 4-hydroxylase, prolyl-4-hydroxylase, p4ha1, egln3, p4ha2, hypoxia-inducible factor prolyl hydroxylase, hif prolyl hydroxylase, proline hydroxylase, c-p4h, prolyl-4-hydroxylases, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
collagen proline hydroxylase
-
-
-
-
hydroxylase, collagen proline
-
-
-
-
peptidyl proline hydroxylase
-
-
-
-
procollagen prolyl 4-hydroxylase
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-
-
-
procollagen-proline dioxygenase
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-
-
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proline hydroxylase
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-
-
-
proline protocollagen hydroxylase
-
-
-
-
proline, 2-oxoglutarate dioxygenase
-
-
-
-
proline,2-oxoglutarate 4-dioxygenase
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-
-
-
prolyl 4-hydroxylase
prolyl hydroxylase
-
-
-
-
prolyl-glycyl-peptide, 2-oxoglutarate:oxygen oxidoreductase, 4-hydroxylating
-
-
-
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prolylprotocollagen dioxygenase
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-
-
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prolylprotocollagen hydroxylase
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-
-
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protocollagen hydroxylase
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-
-
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protocollagen proline 4-hydroxylase
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-
-
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protocollagen proline dioxygenase
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-
-
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protocollagen proline hydroxylase
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-
-
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protocollagen prolyl hydroxylase
-
-
-
-
additional information
-
the enzyme belongs to the P4H enzyme family of the 2-oxoglutarate-dependent dioxygenases
prolyl 4-hydroxylase
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-
-
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
procollagen L-proline + 2-oxoglutarate + O2 = procollagen trans-4-hydroxy-L-proline + succinate + CO2
reaction mechanism involving ascorbate, which are not required for the hydroxylation reaction part, but for the uncoupled cedarboxylation, overview
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
decarboxylation
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-
-
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redox reaction
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-
-
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oxidation
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-
-
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reduction
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-
-
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hydroxylation
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-
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SYSTEMATIC NAME
IUBMB Comments
procollagen-L-proline,2-oxoglutarate:oxygen oxidoreductase (4-hydroxylating)
Requires Fe2+ and ascorbate.The enzyme, which is located within the lumen of the endoplasmic reticulum, catalyses the 4-hydroxylation of prolines in -X-Pro-Gly- sequences. The 4-hydroxyproline residues are essential for the formation of the collagen triple helix. The enzyme forms a complex with protein disulfide isomerase and acts not only on procollagen but also on more than 15 other proteins that have collagen-like domains.
CAS REGISTRY NUMBER
COMMENTARY
9028-06-2
-
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
procollagen L-proline + 2-oxoglutarate + O2
procollagen trans-4-hydroxy-L-proline + succinate + CO2
-
-
-
?
(L-Pro-L-Pro-Gly)10 + 2-oxoglutarate + O2
(L-Pro-L-Pro-Gly)10-trans-4-hydroxy-L-proline + succinate + CO2
-
-
-
-
r
hypoxia-inducible transcription factor + 2-oxoglutarate + O2
hypoxia-inducible transcription factor trans-4-hydroxy-L-proline + succinate + CO2
procollagen L-proline + 2-oxoglutarate + O2
procollagen trans-4-hydroxy-L-proline + succinate + CO2
additional information
?
-
-
substrate and ligand binding structures, overview
-
-
?
(Pro-Pro-Gly)n + 2-oxoglutarate + O2
(Pro-4-hydroxy-Pro-Gly)n + succinate + CO2
-
n: 1,5,10
n: 1,5,10
?
(Pro-Pro-Gly)n + 2-oxoglutarate + O2
(Pro-4-hydroxy-Pro-Gly)n + succinate + CO2
-
n: 1,5,10
n: 1,5,10
?
hypoxia-inducible transcription factor + 2-oxoglutarate + O2
hypoxia-inducible transcription factor trans-4-hydroxy-L-proline + succinate + CO2
-
i.e. HIF, an alphabetaheterodimer, in which the stability of the alpha-subunit is regulated in an oxygen-dependent manner. Hydroxylation of one or two critical proline residues in the oxygen-dependent degradation domain leads to proteasomal degradation of the protein under normic conditions, while under hypoxic conditions the oxygen-requiring hydroxylation is inhibited and HIF-alpha escapes degradation and dimerizes with HIF-beta, overview
-
-
?
hypoxia-inducible transcription factor + 2-oxoglutarate + O2
hypoxia-inducible transcription factor trans-4-hydroxy-L-proline + succinate + CO2
-
i.e. HIF
-
-
?
procollagen L-proline + 2-oxoglutarate + O2
procollagen trans-4-hydroxy-L-proline + succinate + CO2
-
-
-
-
?
procollagen L-proline + 2-oxoglutarate + O2
procollagen trans-4-hydroxy-L-proline + succinate + CO2
-
-
-
?
procollagen L-proline + 2-oxoglutarate + O2
procollagen trans-4-hydroxy-L-proline + succinate + CO2
-
-
-
?
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
procollagen L-proline + 2-oxoglutarate + O2
procollagen trans-4-hydroxy-L-proline + succinate + CO2
-
-
-
?
hypoxia-inducible transcription factor + 2-oxoglutarate + O2
hypoxia-inducible transcription factor trans-4-hydroxy-L-proline + succinate + CO2
-
i.e. HIF, an alphabetaheterodimer, in which the stability of the alpha-subunit is regulated in an oxygen-dependent manner. Hydroxylation of one or two critical proline residues in the oxygen-dependent degradation domain leads to proteasomal degradation of the protein under normic conditions, while under hypoxic conditions the oxygen-requiring hydroxylation is inhibited and HIF-alpha escapes degradation and dimerizes with HIF-beta, overview
-
-
?
procollagen L-proline + 2-oxoglutarate + O2
procollagen trans-4-hydroxy-L-proline + succinate + CO2
procollagen L-proline + 2-oxoglutarate + O2
procollagen trans-4-hydroxy-L-proline + succinate + CO2
-
-
-
-
?
procollagen L-proline + 2-oxoglutarate + O2
procollagen trans-4-hydroxy-L-proline + succinate + CO2
-
-
-
?
procollagen L-proline + 2-oxoglutarate + O2
procollagen trans-4-hydroxy-L-proline + succinate + CO2
-
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Fe2+
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
poly(L-proline)
-
inhibitor, recombinant type II enzyme tetramer, MW: 7000 and 44000
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
LY83583
might increase the enzymatic activity of prolyl 4-hydroxylases to increase type I collagen maturation. LY83583 activated prolyl 4-hydrolases differed from ascorbate-activated prolyl 4-hydroxylase in two aspects: (1) LY83583 activats both P4HA1 and P4HA2 involved in collagen maturation whereas ascorbate mainly stimulats P4HA1 in collagen maturation, (2) LY83583 does not induce N259 glycosylation on P4HA1 as ascorbate does
LY83583
might increase the enzymatic activity of prolyl 4-hydroxylases to increase type I collagen maturation. LY83583 activated prolyl 4-hydrolases differs from ascorbate-activated prolyl 4-hydroxylase in two aspects: (1) LY83583 activats both P4HA1 and P4HA2 involved in collagen maturation whereas ascorbate mainly stimulats P4HA1 in collagen maturation, (2) LY83583 does not induce N259 glycosylation on P4HA1 as ascorbate does
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
-
represents 80% of total enzyme activity, the type II enzyme represents the main enzyme form
-
represents at least about 70% of the total enzyme activity, the type II enzyme represents the main enzyme form
additional information
analysis of P4Halpha1 expression during the pathological course of atherosclerotic plaque development, and effect of P4Ha1 overexpression on vulnerability of early and advanced plaque in apolipoprotein E-deficient (ApoE2/2) mice, overview
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
physiological function
malfunction
-
PHD1-/- mice have statistically non-significant reductions in infarct volumes following middle cerebral artery occlusion compared with their littermates at this time-point in this model
malfunction
-
PHD2+/- mice have significantly increased microvessel density, improved cerebral blood flow on reperfusion, and show significantly better functional outcomes and higher locomotor activity associated with significantly fewer apoptotic cells in the penumbra and significantly less blood-brain-barrier disruption with a trend to reduced infarct volumes 24 h after the middle cerebral artery occlusion than littermate controls
malfunction
after 2 weeks of a treatment with lentivirus-mediated P4Halpha1 construct that is transfected in carotid plaque induced in mice (atherosclerotic plaques in ApoE-/- mice) by perivascular collar placement, both early and advanced plaque exhibit stable characteristics, with increased collagen and smooth muscle cell content, reduced macrophage content, and no change in lipid content. Lenti-P4Ha1 treatment of early and advanced plaque substantially increases interstitial collagen content in the fibrous cap of plaque. It increases the carotid plaque size and the relative en face lesion area of the aorta in early but not advanced plaque, with reduced phosphatase and tensin homologue expression. The treatment reduces the expression of inflammatory cytokines and the production and activity of matrix metalloproteinase-9 and -2 in both early and advanced plaque. P4Halpha1 overexpression has a differential effect at various stages of plaque pathological progression
malfunction
overexpression of prolyl-4-hydroxylase-alpha1 stabilizes but increases shear stress-induced atherosclerotic plaque in apolipoprotein E-deficient mice. After 2 weeks of lenti-P4Halpha1 treatment both low and oscillatory shear stress-induced plaques increase collagen and the thickness of fibrous cap and decreases macrophage accumulation but show no change in lipid accumulation
malfunction
knockout of either P4ha1 or P4ha2 greatly reduces LY83583-stimulated type I collagen maturation whereas silencing of both P4ha1 and P4ha2 completely blocks LY83583-induced type I collagen maturation
physiological function
-
4-hydroxylation of proline is essential for the thermal stability of collagen triple helices, non-hydroxylated collagen polypeptide chains cannot form functional molecules in vivo. The enzyme also acts as hypoxia-inducible transcription factor, HIF, and occurs in three different isozyme forms
physiological function
prolyl-4-hydroxylase (P4H) plays a central role in the synthesis of all known types of collagens, which are the most abundant constituent of the extracellular matrix in atherosclerotic plaque. Isozyme P4Halpha1 is a rate-limiting enzyme and is essential for collagen maturation and secretion
physiological function
prolyl-4-hydroxylase-alpha1 improves the stability of advanced plaques but accelerates the atherosclerotic lesion formation of early plaques. Analysis of P4Halpha1 expression during the pathological course of atherosclerotic plaque development, and effect of P4Ha1 overexpression on vulnerability of early and advanced plaque in apolipoprotein E-deficient (ApoE2/2) mice, overview
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). P4HA3_MOUSE
542
0
60975
Swiss-Prot
Secretory Pathway (Reliability: 1)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
tetramer
additional information
-
the beta-subunit is identical to the beta-subunit of the chaperone protein disulfide isomerase, EC 5.3.4.1. The beta-subunit is responsible for keeping the catalytic alpha-subunit active, in non-aggregated conformation and for retaining the enzyme within the lumen of the endoplasmic reticulum via its C-terminal retention signal
tetramer
-
newborn, SDS-PAGE, due to a larger carbohydrate content the alpha-subunit also exists in larger forms
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
recombinant lentiviral-based overexpression of prolyl-4-hydroxylase-alpha1 in mice, the plaques show increased collgane accumulation but no difference of lipid accumulation. The protein expressions of TGF-beta1 are higher in lenti-P4Ha1 mice than in mock or lenti-EGFP mice. Overexpression of P4Ha1 reduced macrophage infiltration
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
separation of the enzyme from the inactive precursor of the enzyme, using ammonium sulfate precipitation and column chromatography on DEAE-Sephadex A-50 and Agarose A-1.5m columns
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
cloning of the alpha-I subunit and of a second mouse alpha-subunit isoform, termed the alpha-II subunit, expression of the alpha-II subunit together with human protein disulfide isomerase/beta subunit in insect cells by baculovirus vectors
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
P4H alphaII or alphaIII null mice with 20% of wild-type enzyme activity do not show an abnormal phenotype, while P4H alpha I null mutants die at day E10.5 and show an overall developmental delay and rupture of the basement membranes due to a lack of collgane IV, overview
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
medicine
enzyme P4Halpha1 overexpression might be a potential therapeutic target in stabilizing vulnerable plaques to prevent rupture and erosion of atherosclerotic plaque and thus thrombosis
medicine
P4Halpha1 overexpression might be a valuable therapeutic modality in stabilizing advanced but not early plaque because of the adverse event of accelerated lesion formation
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Kivirikko, K.I.; Myllyl, R.; Pihlajaniemi, T.
Protein hydroxylation: prolyl 4-hydroxylase, an enzyme with four cosubstrates and a multifunctional subunit
FASEB J.
3
1609-1617
1989
Gallus gallus, Homo sapiens, Mus musculus, Volvox carteri
Kivirikko, K.I.; Myllyl, R.
Recent developments in posttranslational modification: intracellular processing
Methods Enzymol.
144
96-114
1987
Gallus gallus, Homo sapiens, Mus musculus
McGee, J.O'D.; Udenfriend, S.
Partial purification and characterization of peptidyl proline hydroxylase precursor from mouse fibroblasts
Arch. Biochem. Biophys.
152
216-221
1972
Mus musculus
Helaakoski, T.; Annunen, P.; Vuori, K.; MacNeil, I.A.; Pihlajaniemi, T.; Kivirikko, K.I.
Cloning, baculovirus expression, and characterization of a second mouse prolyl 4-hydroxylase a-subunit isoform: formation of an a2b2 tetramer with the protein disulfide-isomerase/b subunit
Proc. Natl. Acad. Sci. USA
92
4427-4431
1995
Homo sapiens, Mus musculus
Annunen, P.; Autio-Harmainen, H.; Kivirikko, K.I.
The novel type II prolyl 4-hydroxylase is the main enzyme form in chondrocytes and capillary endothelial cells, whereas the type I enzyme predominates in most cells
J. Biol. Chem.
273
5989-5992
1998
Homo sapiens, Mus musculus
Kukkola, L.; Hieta, R.; Kivirikko, K.I.; Myllyharju, J.
Identification and characterization of a third human, rat, and mouse collagen prolyl 4-hydroxylase isoenzyme
J. Biol. Chem.
278
47685-47693
2003
Rattus norvegicus (Q6W3E9), Mus musculus (Q6W3F0), Mus musculus, Homo sapiens (Q7Z4N8), Homo sapiens
Myllyharju, J.
Prolyl 4-hydroxylases, key enzymes in the synthesis of collagens and regulation of the response to hypoxia, and their roles as treatment targets
Ann. Med.
40
402-417
2008
Caenorhabditis elegans, Chlamydomonas reinhardtii, Drosophila melanogaster, Homo sapiens, Mus musculus, Rattus norvegicus
Chen, R.L.; Nagel, S.; Papadakis, M.; Bishop, T.; Pollard, P.; Ratcliffe, P.J.; Pugh, C.W.; Buchan, A.M.
Roles of individual prolyl-4-hydroxylase isoforms in the first 24 hours following transient focal cerebral ischaemia: insights from genetically modified mice
J. Physiol.
590
4079-4091
2012
Mus musculus
Cao, X.Q.; Liu, X.X.; Li, M.M.; Zhang, Y.; Chen, L.; Wang, L.; Di, M.X.; Zhang, M.
Overexpression of prolyl-4-hydroxylase-alpha1 stabilizes but increases shear stress-induced atherosclerotic plaque in apolipoprotein E-deficient mice
Dis. Markers
2016
1701637
2016
Mus musculus (Q60715), Mus musculus ApoE (Q60715)
Huang, X.; Liu, X.; Song, J.; Wang, L.; Liu, X.; Qu, H.; Wang, S.; Zhang, C.; Zhang, Y.; Zhang, M.
Prolyl-4-hydroxylase-alpha1 improves the stability of advanced plaques but accelerates the atherosclerotic lesion formation of early plaques
Eur. Heart J.
17
C49-C58
2015
Mus musculus (Q60715)
-
Song, W.; Yang, C.; Zhu, C.; Morris, P.; Zhang, X.
Crystal structure and expression patterns of prolyl 4-hydroxylases from Phytophthora capsici
Biochem. Biophys. Res. Commun.
508
1011-1017
2019
Phytophthora capsici (A0A4P1LYH8), Mus musculus (Q60715), Mus musculus (Q60716), Mus musculus, Phytophthora capsici LT1534 (A0A4P1LYH8)
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