1.14.11.7: procollagen-proline 3-dioxygenase
This is an abbreviated version!
For detailed information about procollagen-proline 3-dioxygenase, go to the full flat file.
Word Map on EC 1.14.11.7
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1.14.11.7
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hypoxia-inducible
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fibrosis
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hydroxyproline
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factor-1
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endothelial
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hydroxylases
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hif-1alpha
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erythropoietin
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anemia
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domain-containing
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lysyl
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ascorbate
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oxygen-dependent
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normoxic
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hippel-lindau
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4-hydroxylase
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imperfecta
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osteogenesis
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dmog
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dimethyloxalylglycine
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bleomycin
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factor-1alpha
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oxygen-sensing
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angiogenic
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2-oxoglutarate-dependent
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hypoxia-responsive
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chick-embryo
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hif-dependent
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hydroxylysine
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hif-prolyl
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roxadustat
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o2-dependent
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bleomycin-induced
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ppib
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polycythemia
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fkbp10
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intratracheal
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3-hydroxylation
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3,4-dihydroxybenzoic
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prolyl-hydroxylase
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hepcidin
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oxygen-sensitive
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1.14.11.2
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hydroxyproline-rich
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col1a2
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serpinh1
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lindau
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l-mimosine
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erythropoiesis-stimulating
- 1.14.11.7
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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
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hydroxyproline-rich
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col1a2
-
serpinh1
-
lindau
- l-mimosine
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erythropoiesis-stimulating
Reaction
Synonyms
LEPRE1, Leprel1, Leprel2, More, oxygenase, protocollagen proline 3-di-, P3H1, P3H2, P3H3, PHD3, proline,2-oxoglutarate 3-dioxygenase, prolyl 3-hydroxylase, prolyl 3-hydroxylase 1, prolyl 3-hydroxylase 2, prolyl 3-hydroxylase-2, prolyl hydroxylase, prolyl-4-hydroxyprolyl-glycyl-peptide, 2-oxoglutarate: oxygen oxidoreductase, 3-hydroxylating, protocollagen proline 3-hydroxylase
ECTree
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General Information
General Information on EC 1.14.11.7 - procollagen-proline 3-dioxygenase
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drug target
malfunction
physiological function
additional information
the enzyme could be considered as a potential target for anti-angiogenesis therapy
drug target
the enzyme could be considered as a potential target for anti-angiogenesis therapy
malfunction
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in case of enzyme defects, 3-hydroxylation of the Pro986 residue is absent or severly reduced. Defects in the genes encoding cartilage-associated protein, CRTAP, or prolyl 3-hydroxylase 1, P3H1/LEPRE1, cause the classical osteogenesis imperfecta, OI, a dominant genetic disorder of connective tissue, overview. Patients with mutations in CRTAP or LEPRE1 have a lethal to severe osteochondrodystrophy that overlaps with Sillence types II and III classical osteogenesis imperfecta but has distinctive features
malfunction
null mutation of the prolyl 3-hydroxylase 1, P3H1/LEPRE1, gene cause OI type VIII, a recessive form of osteogenesis imperfecta with severe to lethal bone dysplasia and overmodification of the type I collagen helical region, overview
malfunction
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a knockdown of P3H2 protein using RNA interference reduces 3-hydroxylation at Pro-944, Pro-707, and the GPP repeat at the C-terminus of the triple helix but not at Pro-986 of the clade A pNalpha1(II) collagen chain. When P3H2 expression is turned off, 3-hydroxylation at residue Pro-944 in the alpha2(V) chain is lost, and 3Hyp occupancy at Pro-707 in alpha2(V) and alpha2(I) chains is significantly reduced
malfunction
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loss-of function studies show that PHD3 serves as a co-activator of NF-kappaB signaling activity in NP cells. PHD3 interacts with, and co-localizes with, p65
malfunction
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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
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silencing PHD3 leads to a significant decrease in TNF-alpha-induced expression of catabolic markers that include ADAMTS5, syndecan4, MMP13, and COX2, and at the same time, there is restoration of aggrecan and collagen type II expression
malfunction
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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
the enzyme acts as a tumor suppressor, with P3H2 being a specific breast-cancer tumour suppressor
physiological function
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role of PHD3 in the apoptosis of cardiac myocytes. PHD3 promotes the apoptosis of H9c2 cells via an interaction with the BH4 domain of Bcl-2, it affects the formation of the BaxBcl-2 complex
physiological function
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by positively controlling NF-kappaB signaling activity, PHD3 promotes the catabolic effects of the inflammatory cytokines on nucleus pulposus cells
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
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
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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
additional information
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PHD3 upregulation contributes to doxorubicin-induced apoptosis in H9c2 cells. Overexpression of PHD3 counteracts the formation of the BaxBcl-2 complex, the BH4 domain of anti-apoptosis protein Bcl-2 is required for its interaction with PHD3. BaxBcl-2 complex formation is significantly reduced in apoptotic H9c2 cells in which PHD3 is overexpressed compared to the apoptotic H9c2 cells with native PHD3 levels