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drug target
C-P4H is a potential diagnostic marker and therapeutic target for cancer patients
drug target
targeting collagen P4H is a promising strategy to inhibit tumor progression and sensitize triple-negative breast cancer (TNBC) to chemotherapeutic agents. Inhibition of the enzyme (P4HA1) sensitizes triple-negative breast cancer (TNBC) to the chemotherapeutic agent docetaxel and doxorubicin in xenografts and patient-derived models. It is shown that increased P4HA1 expression correlates with short relapse-free survival in TNBC patients who received chemotherapy
malfunction
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excessive collagen formation is involved in the pathogenesis of fibrosis, e.g. in liver and lung, resulting in abnormal wound healing and deformed tissue architecture
malfunction
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reduced enzyme activity leads to reduced steady-state level of Ago2 protein. Hydroxylation has an impact on Ago2 P-body and stress granule localization, depletion of the C-P4H-I subunits by RNAi or genetic ablation of P4H-alphaI in MEF cells reduced Ago2 P-body localization
malfunction
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pharmacologic or genetic inhibition of PHDs induces autophagy and prevents mammalian target of rapamycin complex 1 (mTORC1) activation by amino acids in a HIF-independent manner
malfunction
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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
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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
mutations, where the hydrogen bonding network that involves the Tyr140 and Trp243 residues is disrupted, lead to major changes in folding of the protein and the size and shape of the substrate binding pocket. Trp243 mutation has major long-range effects
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
silencing P4HA2 expression or treatment with a P4HA inhibitor significantly inhibits cell proliferation and suppresses aggressive phenotypes of breast cancer cells in 3D culture, accompanied by reduced deposition of collagen I and IV. Knockdown of P4HA2 inhibits mammary tumor growth and metastasis to lungs in xenograft models. Increased mRNA levels of P4HA2 correlate with poor clinical outcome in breast cancer patients, which is independent of estrogen receptor status. Kaplan-Meier survival analysis, overview
malfunction
an Arabidopsis AtP4H3 T-DNA knock out mutant line shows higher sensitivity to anoxic treatment possibly due to lower induction of the fermentation pathway genes, ADH and PDC1, and of sucrose synthases, SUS1 and SUS4. This sensitivity to anoxia is accompanied by lower protein levels of AGPs-bound epitopes such as LM14 in the mutant line and induction of extensins-bound epitopes, while the expression levels of the majority of the AGPs genes are stable throughout a low oxygen time course. The lower AGPs content might be related to altered frequency of proline hydroxylation occurrence in the p4h3 line
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
malfunction
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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
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metabolism
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pharmacologic inactivation of EGLN3 hydroxylase results in activation of the canonical NF-kappaB pathway
metabolism
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amino-acid starvation causes depletion of alpha-ketoglutarate that leads to PHD inactivation
metabolism
Q81LZ8
the stabilization of collagen triple-helical structure via prolyl hydroxylation involving the enzyme is the rate-limiting step in collagen biosynthesis
physiological function
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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 a single isozyme form
physiological function
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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 a single isozyme form
physiological function
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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
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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
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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
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collagen prolyl-4-hydroxylases, C-P4Hs, are essential enzymes in the post-translational modification of procollagen. C-P4Hs catalyze the hydroxylation of proline residues at the Yaa positions of (Gly-Xaa-Yaa)n repeats in collagen and other proteins containing collagen-like domains, where Xaa is often proline and Yaa is often hydroxyproline
physiological function
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oxygen-dependent hydroxylation of proline residues in the alpha subunit of hypoxia-inducible transcription factor is central to the hypoxic response in animals. Prolyl hydroxylation of HIFalpha increases its binding to the von Hippel-Lindau protein, thus signaling for degradation via the ubiquitin-proteasome system
physiological function
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P4H is a nonheme iron dioxygenase that catalyzes the posttranslational hydroxylation of (2S)-Pro residues in protocollagen strands. The resulting (2S,4R)-4-hydroxyproline residues are essential for the folding, secretion, and stability of the collagen triple helix
physiological function
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P4H regulates the localization and action of Argonaute proteins, i.e. Ago proteins, essential components of the RNA-induced silencing complexes. Proteins such as Dicer, TRBP, MOV10, RHA, RCK/p54 and KIAA1093 associate with Ago proteins and participate in small RNA processing, RISC loading and localization of Ago proteins in the cytoplasmic messenger RNA processing bodies, mechanism, overview
physiological function
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plant and algal prolyl 4-hydroxylases are key enzymes in the synthesis of cell wall components
physiological function
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stability of collagen's triple-helical structure in mammals requires prolyl-4-hydroxylase activity to form hydroxyproline residues within the collagen chains
physiological function
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egg-laying abnormal-9 prolyl hydroxylases regulate the stability and thereby the activity of the alpha-subunits of hypoxia-inducible factor through its ability to catalyze their hydroxylation. EGLN3 promotes differentiation of C2C12 skeletal myoblasts. EGLN3 is a negative regulator of NF-kappaB, and its prolyl hydroxylase activity is required for this effect. EGLN3 is involved in mediating myogenic differentiation, which is HIF-independent
physiological function
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PHD2 is the major regulator of HIF1alpha stability
physiological function
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PHD2 mediates F-actin assembly involving inhibition of Cof-1 phosphorylation. Isozyme PHD2 is the main isoform regulating HIF-1alpha hydroxylation and thus stability in normoxia
physiological function
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PHD3 appears to be a tumor suppressor in colorectal cancer cells that inhibits IKKbeta/NF-kappaB signaling, independent of its hydroxylase activity
physiological function
Q81LZ8
prolyl 4-hydroxylase catalyzes the post-translational hydroxylation of proline residues and plays a role in collagen production, hypoxia response, and cell wall development
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 Bax-Bcl-2 complex
physiological function
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p23 recruits PHD2 to the HSP90 machinery to facilitate HIF-1hydroxylation
physiological function
collagen prolyl-4-hydroxylase alpha subunit 2 (P4HA2) hydroxylates proline residues in -X-Pro-Gly- sequences. Expression and function of P4HA2 in breast cancer progression, P4HA2 is associated with expression of Col1A1, Col3A1, and Col4A1 during breast cancer development and progression
physiological function
Q81LZ8
prolyl 4-hydroxylases are mononuclear nonheme iron enzymes that catalyze the formation of 4R-hydroxyproline from many different substrates, with various biological implications. P4H is a key player in collagen accumulation. The stabilization of collagen triple-helical structure via prolyl hydroxylation is the rate-limiting step in collagen biosynthesis
physiological function
prolyl-4-hydroxylase (P4H) is a non-heme iron hydroxylase that regio- and stereospecifically hydroxylates proline residues in a peptide chain into R-4-hydroxyproline, which is essential for collagen cross-linking purposes in the human body
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 and matrix metalloproteinases are essential for collagen synthesis and degradation. The enzyme is induced by mechanical stretch on the vessel wall, an important stimulus that also induces collagen remodeling, mechanical stretch increases MMP-2 andP4H alpha1 expression in human aortic smooth muscle cell via AKT-P38 MAPK-JNK signaling, thereby inducing vascular remodeling. .. MMP-2 and P4Halpha1 participate in collagen metabolism induced by pathologic mechanical stretch
physiological function
prolyl-4-hydroxylase alpha1 and matrix metalloproteinases are essential for collagen synthesis and degradation. The enzyme is induced by mechanical stretch on the vessel wall, an important stimulus that also induces collagen remodeling, mechanical stretch increases MMP-2 andP4H alpha1 expression in human aortic smooth muscle cell via AKT-P38 MAPK-JNK signaling, thereby inducing vascular remodeling.. MMP-2 and P4Halpha1 participate in collagen metabolism induced by pathologic mechanical stretch
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
physiological function
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(2S,4R)-4-hydroxyproline residues are essential for the stability of this triple helix. These residues arise from the post-translational modification of (2S)-proline residues by collagen prolyl 4-hydroxylases (CP4Hs)
physiological function
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(2S,4R)-4-hydroxyproline residues are essential for the stability of this triple helix. These residues arise from the post-translational modification of (2S)-proline residues by collagen prolyl 4-hydroxylases (CP4Hs)
physiological function
collagen prolyl 4-hydroxylase (P4H) expression and collagen hydroxylation in cancer cells are necessary for breast cancer progression. By modulating alpha ketoglutarate (alpha-KG) and succinate levels P4HA1 expression reduces proline hydroxylation on hypoxia-inducible factor (HIF) 1alpha, enhancing its stability in cancer cells. Activation of the P4HA/HIF-1 axis enhances cancer cell stemness, accompanied by decreased oxidative phosphorylation and reactive oxygen species (ROS) levels. The enzyme is essential for HIF-1alpha stabilization and triple-negative breast cancer (TNBC)chemoresistance
physiological function
prolyl 4-hydroxylase play central roles in the collagen stabilization, hypoxia sensing, and translational regulation in eukaryotes
physiological function
the enzyme catalyze a prevalent posttranslational modification, the hydroxylation of (2S)-proline residues in protocollagen strands. The ensuing (2S,4R)-4-hydroxyproline residues are necessary for the conformational stability of the collagen triple helix
physiological function
the enzyme catalyze a prevalent posttranslational modification, the hydroxylation of (2S)-proline residues in protocollagen strands. The ensuing (2S,4R)-4-hydroxyproline residues are necessary for the conformational stability of the collagen triple helix
physiological function
the enzyme is essential for the stability. As a key enzyme in collagen synthesis, C-P4H can modulate cancer cell behavior via regulating collagen synthesisy of the collagen triple helix. P4HAs and P4HB are highly expressed in many tumors and participate in cancer progression
physiological function
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prolyl 4-hydroxylase play central roles in the collagen stabilization, hypoxia sensing, and translational regulation in eukaryotes
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physiological function
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prolyl-4-hydroxylase alpha1 and matrix metalloproteinases are essential for collagen synthesis and degradation. The enzyme is induced by mechanical stretch on the vessel wall, an important stimulus that also induces collagen remodeling, mechanical stretch increases MMP-2 andP4H alpha1 expression in human aortic smooth muscle cell via AKT-P38 MAPK-JNK signaling, thereby inducing vascular remodeling. .. MMP-2 and P4Halpha1 participate in collagen metabolism induced by pathologic mechanical stretch
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physiological function
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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
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additional information
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2-oxoglutarate-mediated activation of PHD3 is required for tumor suppression, while PHD2 and HIF1alpha are not required, 2-oxoglutarate does not significantly inhibit tumor growth in PHD3 knockdown xenograft tumors. Reactivating PHD2 in A375 cells has no long-term role in inhibiting tumor growth
additional information
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Endothelin signalling implies HIF-alpha-dependent angiogenesis and tumor cell invasion through PHD2 inhibition in normoxic conditions. Endothelin-1 inhibits PHD2 expression and promoter activity to stabilize HIF-alpha. HIF-1alpha and HIF-2alpha accumulation in response to endothelins is specifically impaired in PHD2 overexpressing cells, indicating that re-expression of PHD2 is sufficient to counteract the ET-1- or ET-3-induced HIF-alpha expression. Knockdown of PHD2 by inhibiting the prolyl hydroxylases with deferoxamine mesylate results in a strong induction of HIF-alpha and VEGF expression
additional information
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exogenous expression of wild-type EGLN3, but not of its catalytically inactive mutant, significantly inhibits NF-kappaB activation induced by overexpressed TRAF2 or IkappaB kinase 2, overview. Deletion of EGLN3 by small interfering RNAs leads to activation of NF-kappaB
additional information
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PHD3 upregulation contributes to doxorubicin-induced apoptosis in H9c2 cells. Overexpression of PHD3 counteracts the formation of the Bax-Bcl-2 complex, the BH4 domain of anti-apoptosis protein Bcl-2 is required for its interaction with PHD3. Bax-Bcl-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
additional information
Q81LZ8
active site structure and substrate recognition, overview
additional information
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active site structure and substrate recognition, overview
additional information
Q81LZ8
ligand docking calculations, substrate and inhibitor binding structure, structure-function analysis, coformations of key active site residues Tyr118, Tyr124, and Phe160 in apoenzyme and ligand-bound enzyme, conformational changes involving residues Tyr118, Tyr124, and Phe160 upon metal and 2-oxoglutarate or malonate binding, detailed overview
additional information
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ligand docking calculations, substrate and inhibitor binding structure, structure-function analysis, coformations of key active site residues Tyr118, Tyr124, and Phe160 in apoenzyme and ligand-bound enzyme, conformational changes involving residues Tyr118, Tyr124, and Phe160 upon metal and 2-oxoglutarate or malonate binding, detailed overview
additional information
the active site of the protein contains two aromatic residues (Tyr140 and Trp243). Trp243 is involved in key protein loop-loop interactions that affect the shape and size of the substrate binding pocket. By contrast, the Tyr140 residue is shown to guide the regio- and stereoselectivity by holding the substrate and ferryl oxidant in a specific orientation through hydrogen bonding and Pi-stacking interactions. The Tyr140 residue is involved in expelling the product from the binding pocket after the reaction is completed. Wild-type and mutant enzymes structure-function analysis by quantum mechanics/molecular mechanics (QM/MM) and molecular dynamics (MD) study, QM/MM optimized hydrogen atom abstraction structures for wild-type and mutants at the C4 positions of the substrate, overview
additional information
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the active site of the protein contains two aromatic residues (Tyr140 and Trp243). Trp243 is involved in key protein loop-loop interactions that affect the shape and size of the substrate binding pocket. By contrast, the Tyr140 residue is shown to guide the regio- and stereoselectivity by holding the substrate and ferryl oxidant in a specific orientation through hydrogen bonding and Pi-stacking interactions. The Tyr140 residue is involved in expelling the product from the binding pocket after the reaction is completed. Wild-type and mutant enzymes structure-function analysis by quantum mechanics/molecular mechanics (QM/MM) and molecular dynamics (MD) study, QM/MM optimized hydrogen atom abstraction structures for wild-type and mutants at the C4 positions of the substrate, overview