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Information on EC 1.14.11.7 - procollagen-proline 3-dioxygenase and Organism(s) Mus musculus and UniProt Accession Q8CG70
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1.14.11.7 procollagen-proline 3-dioxygenaseIUBMB Comments
Requires Fe2+ and ascorbate. The enzyme forms a complex with protein disulfide isomerase, and is located in the endoplasmic reticulum. It modifies proline residues within the procollagen peptide of certain collagen types. The modification is essential for proper collagen triple helix formation.
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Word Map
- 1.14.11.7
-
hypoxia-inducible
- fibrosis
- hydroxyproline
- factor-1
- endothelial
- hydroxylases
- hif-1alpha
- erythropoietin
- anemia
-
domain-containing
-
lysyl
- ascorbate
-
oxygen-dependent
-
normoxic
-
hippel-lindau
-
4-hydroxylase
- imperfecta
-
osteogenesis
- dmog
- dimethyloxalylglycine
- bleomycin
- factor-1alpha
-
oxygen-sensing
-
angiogenic
-
2-oxoglutarate-dependent
-
hypoxia-responsive
-
chick-embryo
-
hif-dependent
- hydroxylysine
-
hif-prolyl
-
roxadustat
-
o2-dependent
-
bleomycin-induced
- ppib
- polycythemia
- fkbp10
-
intratracheal
-
3-hydroxylation
-
3,4-dihydroxybenzoic
-
prolyl-hydroxylase
- hepcidin
-
oxygen-sensitive
-
1.14.11.2
-
hydroxyproline-rich
-
col1a2
-
serpinh1
-
lindau
- l-mimosine
-
erythropoiesis-stimulating
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
[procollagen]-L-proline
+
+
=
[procollagen]-trans-3-hydroxy-L-proline
+
+
Synonyms
prolyl hydroxylase, lepre1, prolyl 3-hydroxylase, leprel1, prolyl 3-hydroxylase 1, prolyl 3-hydroxylase 2, leprel2, prolyl 3-hydroxylase-2, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
oxygenase, protocollagen proline 3-di-
-
-
-
-
P3H1
proline,2-oxoglutarate 3-dioxygenase
-
-
-
-
prolyl 3-hydroxylase
prolyl 3-hydroxylase 1
prolyl-4-hydroxyprolyl-glycyl-peptide, 2-oxoglutarate: oxygen oxidoreductase, 3-hydroxylating
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-
-
-
protocollagen proline 3-hydroxylase
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-
-
-
additional information
prolyl 3-hydroxylase
-
-
-
-
additional information
the enzyme belongs to the proline 3-hydroxylase family
additional information
the enzyme belongs to the proline 3-hydroxylase family
additional information
the enzyme belongs to the proline 3-hydroxylase family
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
decarboxylation
-
-
-
-
redox reaction
-
-
-
-
hydroxylation
-
-
-
-
PATHWAY SOURCE
PATHWAYS
-
-
SYSTEMATIC NAME
IUBMB Comments
[procollagen]-L-proline,2-oxoglutarate:oxygen oxidoreductase (3-hydroxylating)
Requires Fe2+ and ascorbate. The enzyme forms a complex with protein disulfide isomerase, and is located in the endoplasmic reticulum. It modifies proline residues within the procollagen peptide of certain collagen types. The modification is essential for proper collagen triple helix formation.
CAS REGISTRY NUMBER
COMMENTARY
63551-75-7
-
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
L-proline-[collagen] + O2
3-hydroxy-L-proline-[collagen]
-
-
-
?
L-proline-[collagen] + O2
3-hydroxy-L-proline-[collagen]
-
-
-
?
procollagen + 2-oxoglutarate + O2
procollagen trans-3-hydroxy-L-proline + succinate + CO2
-
-
-
-
?
procollagen L-proline + 2-oxoglutarate + O2
procollagen trans-3-hydroxy-L-proline + succinate + CO2
-
P3H1 catalyzes the 3-hydroxylation of specific proline residues in procollagen I
-
-
?
[procollagen]-L-proline + 2-oxoglutarate + O2
[procollagen]-trans-3-hydroxy-L-proline + succinate + CO2
[procollagen]-L-proline + 2-oxoglutarate + O2
[procollagen]-trans-3-hydroxy-L-proline + succinate + CO2
-
-
-
?
[procollagen]-L-proline + 2-oxoglutarate + O2
[procollagen]-trans-3-hydroxy-L-proline + succinate + CO2
prolyl 3-hydroxylation in lens capsule, prolyl 3-hydroxylation at Pro602 from alpha1(IV) and Pro197 from alpha2(IV). Pro707 site in alpha1(I) is a tissue-specific substrate unique to P3h2
-
-
?
[procollagen]-L-proline + 2-oxoglutarate + O2
[procollagen]-trans-3-hydroxy-L-proline + succinate + CO2
Residue alpha1(I) K930 is 98% hydroxylated and non-glycosylated in both genotypes and alpha1(I)K87 is 92% hydroxylated in wild-type and 93% in Lepre1H662A/H662A
-
-
?
[procollagen]-L-proline + 2-oxoglutarate + O2
[procollagen]-trans-3-hydroxy-L-proline + succinate + CO2
type IV collagen
-
-
?
[procollagen]-L-proline + 2-oxoglutarate + O2
[procollagen]-trans-3-hydroxy-L-proline + succinate + CO2
collagen from bovine tissue. 3-hydroxyproline occupancy in collagens from bovine and mouse tissues, overview
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-
?
additional information
?
-
type IV collagen contains more prolyl 3-hydroxylation sites than any other collagen types
-
-
?
additional information
?
-
-
type IV collagen contains more prolyl 3-hydroxylation sites than any other collagen types
-
-
?
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
L-proline-[collagen] + O2
3-hydroxy-L-proline-[collagen]
-
-
-
?
L-proline-[collagen] + O2
3-hydroxy-L-proline-[collagen]
-
-
-
?
procollagen L-proline + 2-oxoglutarate + O2
procollagen trans-3-hydroxy-L-proline + succinate + CO2
-
P3H1 catalyzes the 3-hydroxylation of specific proline residues in procollagen I
-
-
?
[procollagen]-L-proline + 2-oxoglutarate + O2
[procollagen]-trans-3-hydroxy-L-proline + succinate + CO2
[procollagen]-L-proline + 2-oxoglutarate + O2
[procollagen]-trans-3-hydroxy-L-proline + succinate + CO2
-
-
-
?
[procollagen]-L-proline + 2-oxoglutarate + O2
[procollagen]-trans-3-hydroxy-L-proline + succinate + CO2
prolyl 3-hydroxylation in lens capsule, prolyl 3-hydroxylation at Pro602 from alpha1(IV) and Pro197 from alpha2(IV). Pro707 site in alpha1(I) is a tissue-specific substrate unique to P3h2
-
-
?
[procollagen]-L-proline + 2-oxoglutarate + O2
[procollagen]-trans-3-hydroxy-L-proline + succinate + CO2
Residue alpha1(I) K930 is 98% hydroxylated and non-glycosylated in both genotypes and alpha1(I)K87 is 92% hydroxylated in wild-type and 93% in Lepre1H662A/H662A
-
-
?
[procollagen]-L-proline + 2-oxoglutarate + O2
[procollagen]-trans-3-hydroxy-L-proline + succinate + CO2
type IV collagen
-
-
?
additional information
?
-
type IV collagen contains more prolyl 3-hydroxylation sites than any other collagen types
-
-
?
additional information
?
-
-
type IV collagen contains more prolyl 3-hydroxylation sites than any other collagen types
-
-
?
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
additional information
additional information
isozyme expression analysis, overview, no expression in skeletal muscle
additional information
isozyme expression analysis, overview, no expression in skeletal muscle
additional information
isozyme expression analysis, overview, no expression in skeletal muscle
additional information
-
isozyme expression analysis, overview, no expression in skeletal muscle
additional information
isozyme expression analysis, overview, no expression in brain and skeletal muscle
additional information
isozyme expression analysis, overview, no expression in brain and skeletal muscle
additional information
isozyme expression analysis, overview, no expression in brain and skeletal muscle
additional information
-
isozyme expression analysis, overview, no expression in brain and skeletal muscle
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
drug target
the enzyme could be considered as a potential target for anti-angiogenesis therapy
malfunction
physiological function
additional information
-
importance of P3H1 to bone structure and development. Mutations in the gene encoding for prolyl 3-hydroxylase 1 can cause a severe, recessive form of osteogenesis imperfecta, a skeletal disorder, minimal 3-hydroxylation of key proline residues in type I collagen as a result of P3H1 deficiency. Prolyl 3-hydroxylase 1 null mice display abnormalities in fibrillar collagen-rich tissues such as tendons, skin, and bones, e.g. abnormalities in collagen fibril ultrastructure in tendons, and alterations in skin architecture, as well as in developing limbs, phenotypes, detailed overview. Collagen secretion rate is decreased in P3H1 null fibroblasts
malfunction
-
PHD3-/- mice have lower cerebral blood flow after reperfusion than wild-type littermates but comparable functional outcomes, suggesting that deleterious haemodynamic effects are counteracted by alternative neuroprotective benefits in this circumstance
malfunction
-
type I collagen extracted from tendon, skin, and bone of wild type and prolyl 3-hydroxylase 1 (P3H1) null mice show distinct patterns of 3-hydroxylation and glycosylation of hydroxylysine residues. The D-period of collagen fibrils is not affected by the lack of 3-hydroxyproline or increasing amounts of hydroxylysine glycosylation. Only small differences are seen in the fibril diameter of newborn mice tail tendons as compared with the severe disorganization found in adult P3H1 null mice, implicating the lateral growth of fibrils in the phenotype
malfunction
mutations in LEPREL1, the gene encoding prolyl 3-hydroxylase-2 (P3H2), cause severe nonsyndromic myopia. Collagens I and IV from P3h2-null mouse eye tissues are significantly reduced in 3-hydroxylation compared with wild-type littermates. Loss of P3h2 causes altered collagen prolyl 3-hydroxylation from multiple tissues, e.g. leading to structural abnormalities in multiple eye tissues, but particularly sclera, causing progressive myopia. Phenotype, overview
malfunction
mutations in the genes encoding cartilage associated protein (CRTAP) and prolyl 3-hydroxylase 1 (LEPRE1) are the causes of recessive osteogenesis imperfecta. The absence of the post-translational modification, 3-hydroxylation of Pro986of collagen, may disrupt protein-protein interactions integral for proper collagen folding and lead to collagen over-modification. absence of one results in degradation of the other. P3H1 and CRTAP stabilize each other and absence of one results in degradation of the other, hypomorphic or loss of function mutations of either gene cause loss of the whole complex and its associated functions. Generated mutant mice carrying a single amino acid substitution in the catalytic site of P3h1 (Lepre1H662A) show abolished P3h1 activity but retain ability to form a complex with Crtap and thus the collagen chaperone function. The mutant mice show absence of prolyl 3-hydroxylation at Pro986 of the alpha1(I) and alpha1(II) collagen chains but no significant over-modification at other collagen residues. They are normal in appearance, have no growth defects and normal cartilage growth plate histology but show decreased trabecular bone mass. This mouse model recapitulates elements of the bone phenotype of osteogenesis imperfecta but not the cartilage and growth phenotypes caused by loss of the prolyl 3-hydroxylation complex. Differential tissue consequences due to selective inactivation of P3H1 hydroxylase activity versus complete ablation of the prolyl 3-hydroxylation complex
malfunction
P3H2-null mice are embryonic-lethal by embryonic day 8.5. The mechanism of the unexpectedly early lethality involves the interaction of non-3-hydroxylated embryonic type IV collagen with the maternal platelet-specific glycoprotein VI (GPVI). This interaction results in maternal platelet aggregation, thrombosis of the maternal blood, and death of the embryo. The phenotype is completely rescued by producing double knockouts of P3H2 and GPVI. Double nulls are viable and fertile. Epigenetic silencing of P3H2 in breast cancers implies that the interaction between GPVI and non3-hydroxylated type IV collagen might also play a role in the progression of malignant tumors and metastasis
physiological function
cartilage associated protein (CRTAP) and prolyl 3-hydroxylase 1 (P3H1) , together with cyclophilin B, form a complex that 3-hydroxylates a single proline residue on the alpha1(I) chain (Pro986) and has cis/trans isomerase (PPIase) activity essential for proper collagen folding. Prolyl 3-hydroxylation of Pro986 is not required for the structural stability of collagen. P3H1 and CRTAP stabilize each other and absence of one results in degradation of the other
physiological function
role for prolyl 3-hydroxylase-2, P3H2, in collagen IV prolyl 3-hydroxylation. Collagen IV is found in many tissues in the eye, including lens capsule, epidermal and endodermal membranes of the cornea, and the inner limiting membrane and Bruchs membrane of the retina
physiological function
role of prolyl 3-hydroxylation in type IV collagen. Subendothelial collagens bear platelet-specific glycoprotein VI, GPVI, binding sites that initiate platelet aggregation upon blood exposure during injuries. In type IV collagen, these sites are normally 3-hydroxylated. Prolyl 3-hydroxylation of type IV collagen has an important function preventing maternal platelet aggregation in response to the early developing embryo. 3-Hydroxylation of type IV collagen is indispensable for embryonic development in mice
physiological function
P3H2 is involved in formation of new vessels. The enzyme catalyzes the post-translational formation of 3-hydroxyproline on collagens, mainly on type IV. Through its activity on type IV collagen, the enzyme is essential for angiogenesis properties of endothelial cells in vitro by performing experiments of gain- and loss-of-function. Overexpression of P3H2 induces a more condensed status of Collagen IV, accompanied by an alignment of the cells along the Collagen IV bundles, so towards an evident pro-angiogenic status
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). P3H3_MOUSE
732
0
81701
Swiss-Prot
Secretory Pathway (Reliability: 1)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
D592A
site-directed mutagenesis, the mutant is able to rescue CRTAP stability
H590A
site-directed mutagenesis, the mutant is able to rescue CRTAP stability. Hydroxylation status at different collagen sites in mutant mice, overview. Residue alpha1(I) K930 is 98% hydroxylated and non-glycosylated in both genotypes and alpha1(I)K87 is 92% hydroxylated in wild-type and 93% in Lepre1H662A/H662A. Collagen fibril ultrastructure, secretion rate, and steady-state levels
H662A
site-directed mutagenesis, generation of mutant mice, phenotype analysis, detailed overview. The mutant is able to rescue CRTAP stability, but Lepre1H662A/H662A mice lack Pro986 collagen hydroxylation
R672A
site-directed mutagenesis, the mutant is able to rescue CRTAP stability
additional information
additional information
construction of P3H2-null mice, the mutants are embryonic-lethal by embryonic day 8.5. The mechanism of the unexpectedly early lethality involves the interaction of non-3-hydroxylated embryonic type IV collagen with the maternal platelet-specific glycoprotein VI (GPVI). This interaction results in maternal platelet aggregation, thrombosis of the maternal blood, and death of the embryo. The phenotype is completely rescued by producing double KOs of P3H2 and GPVI. Double nulls are viable and fertile. Epigenetic silencing of P3H2 in breast cancers implies that the interaction between GPVI and non3-hydroxylated type IV collagen might also play a role in the progression of malignant tumors and metastasis
additional information
generation of mutant mice with mutations in LEPREL1, the gene encoding prolyl 3-hydroxylase-2 (P3H2), causing severe nonsyndromic myopia, phenotype, overview
additional information
-
generation of mutant mice with mutations in LEPREL1, the gene encoding prolyl 3-hydroxylase-2 (P3H2), causing severe nonsyndromic myopia, phenotype, overview
additional information
P3H1s mutants H590A, D592A, H662A, or R672A are able to restore the stability of CRTAP in cell culture
additional information
-
P3H1s mutants H590A, D592A, H662A, or R672A are able to restore the stability of CRTAP in cell culture
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
cartilage associated protein (CRTAP) and prolyl 3-hydroxylase 1 (P3H1) stabilize each other in protein-protein interaction, absence of one results in degradation of the other
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Morello, R.; Bertin, T.K.; Chen, Y.; Hicks, J.; Tonachini, L.; Monticone, M.; Castagnola, P.; Rauch, F.; Glorieux, F.H.; Vranka, J.; Baechinger, H.P.; Pace, J.M.; Schwarze, U.; Byers, P.H.; Weis, M.; Fernandes, R.J.; Eyre, D.R.; Yao, Z.; Boyce, B.F.; Lee, B.
CRTAP is required for prolyl 3- hydroxylation and mutations cause recessive osteogenesis imperfecta
Cell
127
291-304
2006
Mus musculus
Vranka, J.; Stadler, H.S.; Baechinger, H.P.
Expression of prolyl 3-hydroxylase genes in embryonic and adult mouse tissues
Cell Struct. Funct.
34
97-104
2009
Mus musculus (Q3V1T4), Mus musculus (Q8CG70), Mus musculus (Q8CG71), Mus musculus
Vranka, J.A.; Pokidysheva, E.; Hayashi, L.; Zientek, K.; Mizuno, K.; Ishikawa, Y.; Maddox, K.; Tufa, S.; Keene, D.R.; Klein, R.; Baechinger, H.P.
Prolyl 3-hydroxylase 1 null mice display abnormalities in fibrillar collagen-rich tissues such as tendons, skin, and bones
J. Biol. Chem.
285
17253-17262
2010
Mus musculus
Pokidysheva, E.; Zientek, K.D.; Ishikawa, Y.; Mizuno, K.; Vranka, J.A.; Montgomery, N.T.; Keene, D.R.; Kawaguchi, T.; Okuyama, K.; Baechinger, H.P.
Posttranslational modifications in type I collagen from different tissues extracted from wild type and prolyl 3-hydroxylase 1 null mice
J. Biol. Chem.
288
24742-24752
2013
Mus musculus
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
Hudson, D.M.; Joeng, K.S.; Werther, R.; Rajagopal, A.; Weis, M.; Lee, B.H.; Eyre, D.R.
Post-translationally abnormal collagens of prolyl 3-hydroxylase-2 null mice offer a pathobiological mechanism for the high myopia linked to human LEPREL1 mutations
J. Biol. Chem.
290
8613-8622
2015
Mus musculus (Q8CG71), Mus musculus
Homan, E.P.; Lietman, C.; Grafe, I.; Lennington, J.; Morello, R.; Napierala, D.; Jiang, M.M.; Munivez, E.M.; Dawson, B.; Bertin, T.K.; Chen, Y.; Lua, R.; Lichtarge, O.; Hicks, J.; Weis, M.A.; Eyre, D.; Lee, B.H.
Differential effects of collagen prolyl 3-hydroxylation on skeletal tissues
PLoS Genet.
10
e1004121
2014
Mus musculus (Q3V1T4), Mus musculus
Pokidysheva, E.; Boudko, S.; Vranka, J.; Zientek, K.; Maddox, K.; Moser, M.; Faessler, R.; Ware, J.; Baechinger, H.
Biological role of prolyl 3-hydroxylation in type IV collagen
Proc. Natl. Acad. Sci. USA
111
161-166
2014
Mus musculus (Q8CG71)
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