Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.14.11.2 (prolyl hydroxylase)
1,814 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Iron and copper are essential nutrients, excesses or deficiencies of which cause impaired cellular functions and eventually cell death. The metabolic fates of copper and iron are intimately related. Systemic copper deficiency generates cellular iron deficiency, which in humans results in diminished work capacity, reduced intellectual capacity, diminished growth, alterations in bone mineralization, and diminished immune response. Copper is required for the function of over 30 proteins, including superoxide dismutase, ceruloplasmin, lysyl oxidase, cytochrome c oxidase, tyrosinase and dopamine-beta-hydroxylase. Iron is similarly required in numerous essential proteins, such as the heme-containing proteins, electron transport chain and microsomal electron transport proteins, and iron-sulfur proteins and enzymes such as ribonucleotide reductase, prolyl hydroxylase phenylalanine hydroxylase, tyrosine hydroxylase and aconitase. The essentiality of iron and copper resides in their capacity to participate in one-electron exchange reactions. However, the same property that makes them essential also generates free radicals that can be seriously deleterious to cells. Thus, these seemingly paradoxical properties of iron and copper demand a concerted regulation of cellular copper and iron levels. Here we review the most salient characteristics of their homeostasis.
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PMID:Iron and copper metabolism. 1611 86

HIF-1alpha is a transcription factor involved in the cellular adaptation to either hypoxia or iron deficiency. In the presence of oxygen and iron, proline residues in two degradation domains are modified by HIF-1-prolyl hydroxylases (PHDs), resulting in ubiquitination and degradation of HIF-1alpha. Since both molecular oxygen and iron are elements required for this hydroxylation process, HIF-1alpha might be unmodified and stable in conditions lacking oxygen or iron. If so, two degradation domains may respond to hypoxia and iron-depletion in the same way. In this study, however, we found two degradation domains to differentially regulate the stability of HIF-1alpha. The C-terminal domain responded to both hypoxia and iron-depletion, but the N-terminal domain to only iron-depletion. The deletion or point-mutation of the C-terminal domain blunted the hypoxic induction of HIF-1alpha. However, PHD-silencing siRNAs revealed that two degradation domains were not regulated by different types of PHDs. Both domains were regulated mainly by PHD2. The further mutational analysis demonstrated that the ARD1-acetylated motif near the C-terminal degradation domain (CDD) modulates the oxygen-dependent regulation of HIF-1alpha. The oxygen-dependent HIF-1alpha regulation requiring both proline hydroxylation and lysine acetylation may be more complicated than the iron-dependent regulation requiring only proline hydroxylation.
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PMID:Differential responses of two degradation domains of HIF-1alpha to hypoxia and iron deficiency. 1613 9

The ferrous iron and 2-oxoglutarate (2OG) dependent oxygenases catalyse two electron oxidation reactions by coupling the oxidation of substrate to the oxidative decarboxylation of 2OG, giving succinate and carbon dioxide coproducts. The evidence available on the level of incorporation of one atom from dioxygen into succinate is inconclusive. Here, we demonstrate that five members of the 2OG oxygenase family, AlkB from Escherichia coli, anthocyanidin synthase and flavonol synthase from Arabidopsis thaliana, and prolyl hydroxylase domain enzyme 2 and factor inhibiting hypoxia-inducible factor-1 from Homo sapiens all incorporate a single oxygen atom, almost exclusively derived from dioxygen, into the succinate co-product.
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PMID:Incorporation of oxygen into the succinate co-product of iron(II) and 2-oxoglutarate dependent oxygenases from bacteria, plants and humans. 1615 44

Hypoxia-inducible factor (HIF) prolyl 4-hydroxylases are a family of iron- and 2-oxoglutarate-dependent dioxygenases that negatively regulate the stability of several proteins that have established roles in adaptation to hypoxic or oxidative stress. These proteins include the transcriptional activators HIF-1alpha and HIF-2alpha. The ability of the inhibitors of HIF prolyl 4-hydroxylases to stabilize proteins involved in adaptation in neurons and to prevent neuronal injury remains unclear. We reported that structurally diverse low molecular weight or peptide inhibitors of the HIF prolyl 4-hydroxylases stabilize HIF-1alpha and up-regulate HIF-dependent target genes (e.g. enolase, p21(waf1/cip1), vascular endothelial growth factor, or erythropoietin) in embryonic cortical neurons in vitro or in adult rat brains in vivo. We also showed that structurally diverse HIF prolyl 4-hydroxylase inhibitors prevent oxidative death in vitro and ischemic injury in vivo. Taken together these findings identified low molecular weight and peptide HIF prolyl 4-hydroxylase inhibitors as novel neurological therapeutics for stroke as well as other diseases associated with oxidative stress.
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PMID:Hypoxia-inducible factor prolyl 4-hydroxylase inhibition. A target for neuroprotection in the central nervous system. 1622 10

Soluble nickel compounds are likely human carcinogens. The mechanism by which soluble nickel may contribute to carcinogenesis is unclear, though several hypotheses have been proposed. Here we verify the ability of nickel to enter the cell via the divalent metal ion transporter 1 (DMT1) and disturb cellular iron homeostasis. Nickel may interfere with iron at both an extracellular level, by preventing iron from being transported into the cell, and at an intracellular level, by competing for iron sites on enzymes like the prolyl hydroxylases that modify hypoxia inducible factor-1alpha (HIF-1alpha). Nickel was able to decrease the binding of the Von Hippel-Lindau (VHL) protein to HIF-1alpha, indicating a decrease in prolyl hydroxylase activity. The ability of nickel to affect various iron dependent processes may be an important step in nickel dependent carcinogenesis. In addition, understanding the mechanisms by which nickel activates the HIF-1alpha pathway may lead to new molecular targets in fighting cancer.
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PMID:Soluble nickel interferes with cellular iron homeostasis. 1628 25

The eukaryotic translation initiation factor 5A (eIF5A) is the only cellular protein that contains the unique polyamine-derived amino acid, hypusine [Nepsilon-(4-amino-2-hydroxybutyl)lysine]. Hypusine is formed in eIF5A by a novel post-translational modification reaction that involves two enzymatic steps. In the first step, deoxyhypusine synthase catalyzes the cleavage of the polyamine spermidine and transfer of its 4-aminobutyl moiety to the epsilon-amino group of one specific lysine residue of the eIF5A precursor to form a deoxyhypusine intermediate. In the second step, deoxyhypusine hydroxylase converts the deoxyhypusine-containing intermediate to the hypusine-containing mature eIF5A. The structure and mechanism of deoxyhypusine synthase have been extensively characterized. Deoxyhypusine hydroxylase is a HEAT-repeat protein with a symmetrical superhelical structure consisting of 8 helical hairpins (HEAT motifs). It is a novel metalloenzyme containing tightly bound iron at the active sites. Four strictly conserved His-Glu pairs were identified as iron coordination sites. The structural fold of deoxyhypusine hydroxylase is entirely different from those of the other known protein hydroxylases such as prolyl 4-hydroxylase and lysyl hydroxylases. The eIF5A protein and deoxyhypusine/hypusine modification are essential for eukaryotic cell proliferation. Thus, hypusine synthesis represents the most specific protein modification known to date, and presents a novel target for intervention in mammalian cell proliferation.
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PMID:The post-translational synthesis of a polyamine-derived amino acid, hypusine, in the eukaryotic translation initiation factor 5A (eIF5A). 1645 3

Collagen prolyl 4-hydroxylase (C-P4H) alpha-subunit is of regulatory importance in the assembling of C-P4H tetramers, which are necessary for the hydroxylation of procollagen chains. Change in collagen expression by hypoxia or iron diminishment is a significant issue in extracellular matrix remodeling. It was proposed that C-P4H-alpha (I) is regulated at the posttrancriptional level under these conditions. Here we report that the induction of C-P4H-alpha (I) in human fibrosarcoma cells HT1080 by the iron chelator 2,2-dipyridyl is predominantly caused by an enhancement of mRNA stability. This effect is mediated by an increased synthesis and binding of heterogeneous nuclear ribonucleoprotein (hnRNP)-A2/B1, which interacts with a (U)(16) element located in the 3'-untranslated region of C-P4H-alpha (I) mRNA. Luciferase reporter gene assays depending on C-P4H-alpha (I) 3'-untranslated region and co-transfection with hnRNP-A2/B1 provide evidence that the (U)(16) element is necessary and sufficient for posttranscriptional control of C-P4H-alpha (I) synthesis under the analyzed conditions. Further indication for the significance of hnRNP-A2/B1 in C-P4H-alpha (I) induction was obtained by micro array experiments. In a data set representing 686 independent physiological conditions, we found a significant positive correlation between hnRNP-A2/B1 and C-P4H-alpha (I) mRNAs.
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PMID:Heterogeneous nuclear ribonucleoprotein-A2/B1 modulate collagen prolyl 4-hydroxylase, alpha (I) mRNA stability. 1646 61

Deoxyhypusine hydroxylase (DOHH) catalyzes the final step in the post-translational synthesis of hypusine (N(epsilon)-(4-amino-2-hydroxybutyl)lysine) in eIF5A. DOHH is a HEAT-repeat protein with eight tandem helical hairpins in a symmetrical dyad. It contains two potential iron coordination sites (one on each dyad) composed of two strictly conserved His-Glu motifs. The purified human recombinant DOHH was a mixture of active holoenzyme containing 2 mol of iron/mol of DOHH and inactive metal-free apoenzyme. The two species could be distinguished by their different mobilities upon native gel electrophoresis. The DOHH apoenzyme exhibited markedly reduced levels of iron and activity. DOHH activity could be restored only by the addition of Fe2+ to the apoenzyme but not by other metals including Cd2+,Co2+,Cr2+,Cu2+,Mg2+,Mn2+,Ni2+, and Zn2+. The role of the strictly conserved His-Glu residues was evaluated by site-directed mutagenesis. Substitution of any single amino acid in the four His-Glu motifs with alanine abolished the enzyme activity. Of these eight alanine substitutions, six, including H56A, H89A, E90A, H207A, H240A, and E241A, caused a severe reduction in the iron content. Our results provide strong evidence that Fe(II) is the active-site-bound metal critical for DOHH catalysis and that the strictly conserved His-Glu motifs are essential for iron binding and catalysis. Furthermore, the iron to DOHH stoichiometry and dependence of iron binding on each of the four conserved His-Glu motifs suggest a binuclear iron mediated reaction mechanism, distinct from that of other Fe(II)-dependent protein hydroxylases, such as prolyl 4-hydroxylase or lysyl hydroxylases.
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PMID:Deoxyhypusine hydroxylase is a Fe(II)-dependent, HEAT-repeat enzyme. Identification of amino acid residues critical for Fe(II) binding and catalysis [corrected]. 1653 14

Hypoxia-inducible factor-1, HIF1, transcriptionally activates over 200 genes vital for cell homeostasis and angiogenesis. We developed a computational model to gain a detailed quantitative understanding of how HIF1 acts to sense oxygen and respond to hypoxia. The model consists of kinetic equations describing the intracellular variation of 17 compounds, including HIF1, iron, prolyl hydroxylase, oxygen, ascorbate, 2-oxoglutarate, von Hippel Lindau protein and associated complexes. We tested an existing hypothesis of a switch-like change in HIF1 expression in response to a gradual decrease in O2 concentration. Our model predicts that depending on the molecular environment, such as intracellular iron levels, the hypoxic response varies considerably. We show HIF1-activated cellular responses can be divided into two categories: a steep, switch-like response to O2 and a gradual one. Discovery of this dual response prompted comparison of two therapeutic strategies, ascorbate and iron supplementation, and prolyl hydroxylase targeting, to predict under what microenvironments either effectively increases HIF1alpha hydroxylation. Results provide crucial insight into the effects of iron and prolyl hydroxylase on oxygen sensing. The model advances quantitative molecular level understanding of HIF1 pathways--an endeavor that will help elucidate the diverse responses to hypoxia found in cancer, ischemia and exercise.
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PMID:A computational model of intracellular oxygen sensing by hypoxia-inducible factor HIF1 alpha. 1689 21

The mechanisms controlling the expression of the gene encoding for the hormone erythropoietin (EPO) are exemplary for oxygen-regulated gene expression. In humans and other mammals, hypoxia modulates EPO levels by increasing expression of the EPO gene. An association between polycythaemia and people living at high altitudes was first reported more than 100 years ago. Since the identification of EPO as the humoral regulator of red blood cell production and the cloning of the EPO gene, considerable progress has been made in understanding the regulation of EPO gene expression. This has finally led to the identification of a widespread cellular oxygen-sensing mechanism. Central to this mechanism is the transcription factor complex hypoxia-inducible factor (HIF)-1. The abundance and activity of HIF-1, a heterodimer of an alpha- and beta-subunit, is predominantly regulated by oxygen-dependent post-translational hydroxylation of the alpha-subunit. Non-heme ferrous iron containing hydroxylases use dioxygen and 2-oxoglutarate to specifically target proline and an asparagine residue in HIF-1alpha. As such, the three prolyl hydroxylases (prolyl hydroxylase domain-containing protein (PHD) 1, PHD2 and PHD3) and the asparagyl hydroxylase (factor inhibiting HIF (FIH)-1) act as cellular oxygen sensors. In addition to erythropoiesis, HIF-1 regulates a broad range of physiologically relevant genes involved in angiogenesis, apoptosis, vasomotor control and energy metabolism. Therefore, the HIF system is implicated in the pathophysiology of many human diseases. In addition to the tight regulation by oxygen tension, temporal and tissue-specific signals limit expression of the EPO gene primarily to the fetal liver and the adult kidney.
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PMID:Hypoxia-induced erythropoietin production: a paradigm for oxygen-regulated gene expression. 1700 76


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