Human articular cartilage is an avascular tissue, and therefore it functions in a hypoxic environment. Cartilage cells, the chondrocytes, have adapted to this and actually use hypoxia to drive tissue-specific functions. We have previously shown that human chondrocytes enhance cartilage matrix synthesis in response to hypoxia specifically through hypoxia-inducible factor 2alpha (HIF-2alpha)-mediated up-regulation of master regulator transcription factor SOX9, which in turn drives expression of the main cartilage-specific extracellular matrix genes. HIF-alpha isoforms are themselves regulated by specific prolyl hydroxylase domain-containing proteins, which target them for proteosomal degradation. In fact, prolyl hydroxylase domains are the direct oxygen sensors because they require molecular oxygen as a co-substrate. Here, we have identified PHD2 as the dominant isoenzyme regulating HIF-2alpha stability in human chondrocytes. Moreover, specific inhibition of PHD2 using RNA interference-mediated depletion
This study investigated the effects of 2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetic acid (IOX3), a selective small molecule inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylases, on mouse brains subject to transient focal cerebral ischaemia. Male, 8- to 12-week-old C57/B6 mice were subjected to 45 min of middle cerebral artery occlusion (MCAO) either immediately or 24 h after receiving IOX3. Mice receiving IOX3 at 20 mg/kg 24 h prior to the MCAO had better neuroscores and smaller blood-brain barrier (BBB) disruption and infarct volumes than mice receiving the vehicle, whereas those having IOX3 at 60 mg/kg showed no significant changes. IOX3 treatment immediately before MCAO was not neuroprotective. IOX3 up-regulated HIF-1α, and increased EPO expression in mouse brains. In an in vitro BBB model (RBE4 cell line), IOX3 up-regulated HIF-1α and delocalized ZO-1. Pre-treating IOX3 on RBE4 cells 24 h before oxygen-glucose deprivation had a protective effect on endothelial barrier ...
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This study investigated the effects of 2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetic acid (IOX3), a selective small molecule inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylases, on mouse brains subject to transient focal cerebral ischaemia. Male, 8- to 12-week-old C57/B6 mice were subjected to 45 min of middle cerebral artery occlusion (MCAO) either immediately or 24 h after receiving IOX3. Mice receiving IOX3 at 20 mg/kg 24 h prior to the MCAO had better neuroscores and smaller blood-brain barrier (BBB) disruption and infarct volumes than mice receiving the vehicle, whereas those having IOX3 at 60 mg/kg showed no significant changes. IOX3 treatment immediately before MCAO was not neuroprotective. IOX3 up-regulated HIF-1α, and increased EPO expression in mouse brains. In an in vitro BBB model (RBE4 cell line), IOX3 up-regulated HIF-1α and delocalized ZO-1. Pre-treating IOX3 on RBE4 cells 24 h before oxygen-glucose deprivation had a protective effect on endothelial barrier
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Cells exposed to low-oxygen conditions (hypoxia) alter their metabolism to survive. This response, although vital during development and high-altitude survival, is now known to be a major factor in the selection of cells with a transformed metabolic phenotype during tumorigenesis. It is thought that hypoxia-selected cells have increased invasive capacity and resistance to both chemo- and radiotherapies, and therefore represent an attractive target for antitumor therapy. Hypoxia inducible factors (HIFs) are responsible for the majority of gene expression changes under hypoxia, and are themselves controlled by the oxygen-sensing HIF prolyl hydroxylases (PHDs). It was previously shown that mutations in succinate dehydrogenase lead to the inactivation PHDs under normoxic conditions, which can be overcome by treatment with alpha-ketoglutarate derivatives. Given that solid tumors contain large regions of hypoxia, the reactivation of PHDs in these conditions could induce metabolic catastrophe and ...
TY - JOUR. T1 - Reactivating HIF prolyl hydroxylases under hypoxia results in metabolic catastrophe and cell death. AU - Tennant, D.A.. AU - Frezza, C.. AU - MacKenzie, E.D.. AU - Nguyen, Q.D.. AU - Zheng, L.. AU - Selak, M.A.. AU - Roberts, D.L.. AU - Dive, C.. N1 - Strathprints policy is to record up to 8 authors per publication, plus any additional authors based at the University of Strathclyde. More authors may be listed on the official publication than appear in the Strathprints record.. PY - 2009/11/12. Y1 - 2009/11/12. N2 - Cells exposed to low-oxygen conditions (hypoxia) alter their metabolism to survive. This response, although vital during development and high-altitude survival, is now known to be a major factor in the selection of cells with a transformed metabolic phenotype during tumorigenesis. It is thought that hypoxia-selected cells have increased invasive capacity and resistance to both chemo- and radiotherapies, and therefore represent an attractive target for antitumor ...
Hypoxia-inducible factor (HIF) regulates expression of genes involved in adaptation to hypoxia and ischemia. Three prolyl hydroxylases (PHD1-3) underlie oxygen-regulated destruction of HIFalpha chains. We have investigated the organ distribution of the PHDs in the rat, their regulation by hypoxia and changes in local expression after experimental myocardial infarction using RNase protection assays, in situ hybridization and immunohistochemistry. mRNAs of all isoforms were detectable in heart, liver, kidney, brain, testis and lung. In normal animals, highest levels for PHD2 mRNA and PHD3 mRNA were found in myocardium, whereas PHD1 mRNA was detected predominantly in the testis. PHD1 mRNA was constitutively expressed. PHD2 mRNA was induced by hypoxia in the liver and PHD3 mRNA in liver, testis and heart. Overall our results show that PHD2 mRNA is ubiquitously expressed in normal animals, in keeping with a general role in oxygen sensing. PHD1 and 3 mRNA distributions suggest particular roles in testis and
Prolyl 4-hydroxylase (EC 1.14.11.2) catalyses the post-translational formation of 4-hydroxyproline in collagens. The vertebrate enzymes are α2β2 tetramers, their β subunit being identical to protein disulphide isomerase (PDI). The function of the PDI-β subunit in prolyl 4-hydroxylases is not fully understood, but it seems to be that of keeping the highly insoluble α subunits in solution. We report here that expression of the α subunit of human type I prolyl 4-hydroxylase in insect cells together with BiP polypeptide leads to the formation of both soluble and insoluble α-subunit-BiP complexes. Formation of the soluble complexes was evident from (1) a marked increase in the amount of the α subunit in the soluble fraction of the cell homogenates when expressed together with BiP, (2) immunoprecipitation experiments and (3) demonstration of the presence of some of the complexes by polyacrylamide gel electrophoresis under non-denaturing conditions. Formation of the insoluble complexes was ...
Activity of the hypoxia-inducible factor (HIF) complex is controlled by oxygen-dependent hydroxylation of prolyl and asparaginyl residues. Hydroxylation of specific prolyl residues by 2-oxoglutarate (2-OG)-dependent oxygenases mediates ubiquitinylation and proteasomal destruction of HIF-alpha. Hydroxylation of an asparagine residue in the C-terminal transactivation domain (CAD) of HIF-alpha abrogates interaction with p300, preventing transcriptional activation. Yeast two-hybrid assays recently identified factor inhibiting HIF (FIH) as a protein that associates with the CAD region of HIF-alpha. Since FIH contains certain motifs present in iron- and 2-OG-dependent oxygenases we investigated whether FIH was the HIF asparaginyl hydroxylase. Assays using recombinant FIH and HIF-alpha fragments revealed that FIH is the enzyme that hydroxylates the CAD asparagine residue, that the activity is directly inhibited by cobalt(II) and limited by hypoxia, and that the oxygen in the alcohol of the hydroxyasparagine
Administration of triamcinolone diacetate to rats results in a decrease of prolyl hydroxylase activity in organs from animals of different ages. The response of the enzyme activity is dose-dependent, reversible, independent of endocrine function (except for the response of the liver enzyme in hypophysectomized rats), and dependent on the number of daily injections. The decrease in enzyme activity is paralleled by a decrease in the amount of enzyme protein as measured by immunoassay. These results indicate that prolyl hydroxylase is decreased in a wide spectrum of tissues following administration of anti-inflammatory steroids. Furthermore, these findings suggest that one of the effects of this class of therapeutically used drugs on connective tissue metabolism may be mediated by a decrease in the prolyl hydroxylation step of collagen biosynthesis.. ...
Researchers have developed an in vitromodel to mimic hemorrhagic stroke using hemin, which induces cell death in various neuronal cell types that is rescued by PHD inhibitors.
Ivanhoe Newswire) -- The name of the drug is FG-2216, and its designed to stimulate production of the hormone erythropoietin (EPO) in dialysis patients. In fact, its the worlds first oral drug for the treatment of kidney disease-related anemia; its a hypoxia inducible factor prolyl hydroxylase inhibitor (HIF-PHI) that stabilizes the "master switch," which normally tells the body to produce EPO in response to low oxygen levels.. Anemia, one of the more common blood disorders, is caused by low production of EPO, which has been assumed to result from damage to the kidney cells that produce EPO.. "Our study clearly shows that this may not be the case, and that the kidneys of patients on dialysis retain significant ability to produce erythropoietin," which Wanja M. Bernhardt, MD, Department of Nephrology, University hospital Erlangen, Germany, was quoted as saying. "Renal anemia seems to result from disturbed regulation rather than lost production capacity of the hormone.. Treatment with FG-2216 ...
Parkinsons Disease is a peer-reviewed, Open Access journal that publishes original research articles, review articles, and clinical studies related to the epidemiology, etiology, pathogenesis, genetics, cellular, molecular and neurophysiology, as well as the diagnosis and treatment of Parkinsons disease.
Prolyl hydroxylases (PHDs) are dioxygenases that use oxygen as a co-substrate to hydroxylate proline residues. Three PHD isoforms (PHD1, PHD2 and PHD3) have been identified in mammalian cells. PHD3 expression is upregulated in some cardiac diseases s
Hypoxia activates transcription of genes necessary for adaptation to low oxygen.1,2 The best described response system uses hypoxia-inducible factors (HIFs) composed of the constitutively expressed subunit HIF-1β bound to labile subunits HIF-1α or HIF-2α, forming HIF-1 or HIF-2, respectively.3 HIF expression is regulated by a family of prolyl hydroxylases, PHD1, PHD2, and PHD3, that sense oxygen tension through its binding to an associated iron atom.4,5 When the PHD iron is occupied by O2, these enzymes catalyze a reaction in which one oxygen atom reacts with 2-oxoglutarate to form succinate and CO2 while the other is transferred to a proline residue in a protein substrate, such as HIF-1α, to form a hydroxyproline side chain. Hydroxylation of proline in HIF-1α recruits the von Hippel-Lindau (pVHL) complex, targeting HIF-1α for ubiquitination and proteasomal degradation.6-8 Molecular oxygen is normally rate limiting, and hypoxia causes HIF-1α protein stabilization and accumulation by ...
We performed pharmokinetic/pharmodynamic studies in order to determine the optimal drug delivery dosage regimin in older or younger pre-clinical models for the general prolyl hydroxylase (PHD) inhibitor 3,4-dihydroxybenzoate (DHB). This information guided our decisions regarding dosage in an age-related chronic PD pre-clinical model (inducible glutathione depletion, Chinta et al., 2007). Results indicated that in older pre-clinical models (where neurodegenerative effects are first observed), treatment with DHB at one particular dose, with assessment after 14 days, prevented iron dysregulation and resulted in significant retention of both mitochondrial respiratory function and nigral dopaminergic cell numbers versus saline-treated controls. These data suggest that at this dosage, DHB administration in a chronic, age-related model of the disorder results in neuroprotection similar to those previously observed in the more acute MPTP intoxication model (Lee et al., 2009). ...
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Fully activated innate immune cells are required for effective responses to infection, but their prompt deactivation and removal are essential for limiting tissue damage. Here, we have identified a critical role for the prolyl hydroxylase enzyme Phd2 in maintaining the balance between appropriate, predominantly neutrophil-mediated pathogen clearance and resolution of the innate immune response. We demonstrate that myeloid-specific loss of Phd2 resulted in an exaggerated inflammatory response to Streptococcus pneumonia, with increases in neutrophil motility, functional capacity, and survival. These enhanced neutrophil responses were dependent upon increases in glycolytic flux and glycogen stores. Systemic administration of a HIF-prolyl hydroxylase inhibitor replicated the Phd2-deficient phenotype of delayed inflammation resolution. Together, these data identify Phd2 as the dominant HIF-hydroxylase in neutrophils under normoxic conditions and link intrinsic regulation of glycolysis and glycogen ...
Abstract BACKGROUND: Inhibition of the HIF regulating prolyl hydroxylation domain (PHDs) proteins prior to renal injury (preconditioning) has been shown to protect the kidney via activation of hypoxia-inducible transcription factors (HIF). Application of erythropoietin (EPO), one of the HIF target genes, has also been shown to be nephroprotective, and it remains unclear to what extent…
Effect of DTT on prolyl oligopeptidase levels in plasma from healthy and RR-MS patients. POP activity in plasma from healthy controls (white bar) and RR-MS pati
Hydroxyproline and hydroxylysine are not utilized for collagen synthesis by smooth muscle cells as well as by fibro-, chondro-, osteoblasts and other collagen synthesizing cells. First, the peptide...
In addition to mediating cellular responses to hypoxia, the HIF system has major functions in oxygenated cells ( 12) and can be activated by a range of nonhypoxic stimuli ( 1, 13- 15). To better understand these processes, we analyzed induction of HIF in a cell line model of monocyte/macrophage differentiation. PMA treatment of monocytic cell lines causes them to adhere, cease proliferation, and acquire characteristics of cells of the macrophage lineage ( 6, 33, 34). We show clear induction of HIF-1α in these cells, despite apparently normoxic culture conditions, and show that this is associated with lack of hydroxylation of at least one of the prolyl residues that normally target normoxic HIF-α for destruction.. PMA did not act by reducing expression of the PHD enzymes that catalyze HIF prolyl hydroxylation. Indeed, PHD2 is thought to be the predominant enzyme regulating HIF-1α levels in normoxia ( 24), especially when relatively more abundant than the other PHD enzymes ( 35), and PHD2 ...
Homo sapiens hypoxia-inducible factor prolyl 4-hydroxylase (PH-4), transcript variant 1, mRNA. (H00054681-R03) - Products - Abnova
Homo sapiens hypoxia-inducible factor prolyl 4-hydroxylase (PH-4), transcript variant 3, mRNA. (H00054681-R02) - Products - Abnova
Molekulare Sauerstoff-Regulation: Bedeutung für Wachstum und Ausbreitung kolorektaler Karzinome Die Verfügbarkeit von Sauerstoff ist für das Wachstum und die Ausbreitung solider Tumoren unerlässlich. Darum vermögen sich Tumorzellen an Sauerstoffmangel anzupassen. Diese Anpassungsmechanismen werden von Hypoxie-Induzierbaren Transkriptionsfaktoren (HIFs) vermittelt. Bei ausreichendem Sauerstoffangebot hingegen bewirken drei HIF Prolyl-Hydroxylase Enzyme, PHD1, PHD2 und PHD3, den Abbau von HIF. Die PHD Enzyme fungieren somit als molekulare Sauerstoff-Sensoren. Als Enzyme der molekularen Sauerstoff-Regulation stellen sie zudem ein attraktives pharmakologisches Target zur Behandlung von Hypoxie-bedingten Erkrankungszuständen dar. Insbesondere lassen aktuelle Forschungsergebnisse vermuten, dass eine Hemmung der PHD Enzyme zu einer Verbesserung der Leberfunktion nach chirurgischer Leber-Teilentfernung führt, welche für die kurative Behandlung kolorektaler Lebermetastasen entscheidend ist. ...
by Brożek, Jan L., MD, PhD and Bousquet, Jean, MD, PhD and Agache, Ioana, MD, PhD and Agarwal, Arnav, BHSc and Bachert, Claus, MD PhD and Bosnic-Anticevich, Sinthia, BPharm, PhD and Brignardello-Petersen, Romina, DDS, MSc, PhD and Canonica, G. Walter, MD and Casale, Thomas, MD and Chavannes, Niels H., MD, PhD and Correia de Sousa, Jaime, MD, PhD and Cruz, Alvaro A and Cuello-Garcia, Carlos A., MD and Demoly, Pascal, MD, PhD and Dykewicz, Mark, MD and Etxeandia-Ikobaltzeta, Itziar, PhD and Florez, Ivan D., MD, MSc and Fokkens, Wytske, MD, PhD and Fonseca, Joao, MD, PhD and Hellings, Peter W., MD, PhD and Klimek, Ludger, MD, PhD and Kowalski, Sergio, MD and Kuna, Piotr, MD, PhD and Laisaar, Kaja-Triin, MD, MPH and Larenas-Linnemann, Désirée E., MD and Lødrup Carlsen, Karin C., MD, PhD and Manning, Peter J., MD and Meltzer, Eli, MD and Mullol, Joaquim, MD, PhD and Muraro, Antonella, MD, PhD and OHehir, Robyn, PhD and Ohta, Ken, MD, PhD and Panzner, Petr, MD, PhD and Papadopoulos, Nikolaos, MD, ...
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Marianne Baernholdt, PhD, MPH, RN, FAAN; Ivora D. Hinton, PhD; Guofen Yan, PhD; Wenjun Xin, MS; Emily Cramer, PhD; & Nancy Dunton, PhD, FAAN (March 15, 2017 ...
須田智、大久保誠二、阿部新、金丸拓也、斉藤智成、神谷信雄、酒巻雅典、三品雅洋、上田雅之、桂研一郎、片山泰朗:椎骨動脈解離による Wallenberg症候群。日医大医会誌 7(4):175-178、2011. ...
Η Αμινά Γκουρίμπ (Bibi Ameenah Firdaus Gurib-Fakim, GCSK, CSK, PhD[6][7] (γενν. στις 17 Οκτωβρίου 1959)[8] είναι επιστήμονας ειδική σε θέματα βιοποικιλότητας και Πρόεδρος του Μαυρίκιου από τον Ιούνιο του 2015 ως τις 23 Μαρτίου 2018. Ως πρόεδρος είναι αρχηγός κράτους και αρχηγός του στρατού. Τον Δεκέμβριο του 2014 προκάλεσε αίσθηση όταν έγινε γνωστή η υποψηφιότητά της με τη συμμαχία Λεπέπ. Έπειτα από την παραίτηση του Κέιλας Πραγκ στις 29 Μαΐου 2015, αμφότεροι ο πρωθυπουργός Άνρουντ Τζάγκνοτ και ο ηγέτης της αντιπολίτευσης Πολ Μπερενζέ, καλωσόρισαν θετικά το διορισμό της, ο οποίος ...
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The HIFs (hypoxia-inducible factors) are a family of heterodimeric transcription factors essential for the adaptation of cells to reduced oxygen supply. Three human PHDs (prolyl hydroxylase domain proteins, PHD1-PHD3) initiate oxygen-dependent degradation of HIF-α-subunits in normoxia. RNA interference directed against PHD2, but not PHD1 or PHD3, is sufficient to stabilize HIF-1α in normoxia. Therefore PHD2 is regarded as the main cellular oxygen sensor. PHD2 itself is up-regulated by hypoxia and may thus limit hypoxic signalling. By sequence analysis, we predicted a promoter approx. 3.5 kb 5′ of the translation start codon and a second promoter located in a CpG island immediately upstream of the coding sequence. A consensus HIF-1-binding site that is conserved in the murine phd2 gene was detected in the CpG island. By electrophoretic mobility-shift assay, we demonstrated binding of HIF-1 to the putative HIF-1-binding site. In luciferase reporter vectors, the isolated upstream promoter was ...
In the present study we sought to determine the effect of CoCl2, an inhibitor of PHD (prolyl hydroxylase domain protein), on the development of AAA (abdominal aortic aneurysm). AAA was induced in C57BL/6 mice by periaortic application of CaCl2 (AAA group). NaCl (0.9%)-treated mice were used as a sham control (SHAM group). Mice were treated with 0.05% CoCl2 in the drinking water (AAA/CoCl2 group). At 1 and 6 weeks after the operation, aortic tissue was excised for further examination. After 6 weeks of CaCl2 treatment, aortic diameter and macrophage infiltration into the aortic adventitia were increased in the AAA group compared with the SHAM group. Treatment with CoCl2 reduced the aneurysmal size and macrophage infiltration compared with the AAA group. Aortic expression of inflammatory cytokines and MCP-1 (monocyte chemoattractant protein-1) and the activities of MMP-9 (matrix metalloproteinase-9) and MMP-2 were enhanced in the AAA group and attenuated in the AAA/CoCl2 group. Expression of ...
Polycythemia is often associated with erythropoietin (EPO) overexpression and defective oxygen sensing. In normal cells, intracellular oxygen concentrations are directly sensed by prolyl hydroxylase domain (PHD)-containing proteins, which tag hypoxia-inducible factor (HIF) α subunits for polyubiquitination and proteasomal degradation by oxygen-dependent prolyl hydroxylation. Here we show that different PHD isoforms differentially regulate HIF-α stability in the adult liver and kidney and suppress Epo expression and erythropoiesis through distinct mechanisms. Although Phd1−/− or Phd3−/− mice had no apparent defects, double knockout of Phd1 and Phd3 led to moderate erythrocytosis. HIF-2α, which is known to activate Epo expression, accumulated in the liver. In adult mice deficient for PHD2, the prototypic Epo transcriptional activator HIF-1α accumulated in both the kidney and liver. Elevated HIF-1α levels were associated with dramatically increased concentrations of both Epo mRNA in ...
OBJECTIVE: Rheumatoid arthritis (RA) is characterized by hypoxia and the expression of hypoxia-inducible transcription factors (HIFs), which coordinate cellular responses to hypoxia. The objective of this study was to analyze the expression and regulation of prolyl hydroxylase domain (PHD) enzymes and factor-inhibiting HIF-1α (FIH-1), which regulate cellular HIF levels, and to study the roles of these enzymes in RA fibroblast-like synoviocytes (RA FLS). METHODS: The expression of PHD and FIH and downstream target genes was assessed by quantitative polymerase chain reaction and Western blotting. A small interfering RNA (siRNA) approach and an in vitro endothelial cell angiogenesis assay were used to analyze the roles of HIF hydroxylases. RESULTS: In human RA FLS, knockdown of PHD-2, but not knockdown of PHD-1 or FIH-1, dramatically augmented HIF-1α expression, modestly increased HIF-2α protein expression under normoxic conditions, and up-regulated HIF-dependent gene expression. In contrast, silencing
Silencing prolyl hydroxylase domain protein 2 (PHD2) promotes the survival of transplanted adipose-derived stem cells (ADSCs) in infarcted hearts and enhances their paracrine function. The promoted survival was HIF-1alpha dependent, while the enhanced paracrine function was associated with NF-kB signaling. ...
Location: Exhibit Hall A The clinical posters will be available on Akebias website (www.akebia.com) in the Media section under the Publications tab. About AKB-6548 AKB-6548 is a once-daily, oral therapy currently in development for the treatment of anemia related to CKD. AKB-6548 is designed to stabilize HIF, a transcription factor that regulates the expression of genes involved with red blood cell (RBC) production in response to changes in oxygen levels, by inhibiting the hypoxia-inducible factor prolyl hydroxylase (HIF-PH) enzyme. AKB-6548 exploits the same mechanism of action used by the body to naturally adapt to lower oxygen availability associated with a moderate increase in altitude. At higher altitudes, the body responds to lower oxygen availability with increased production of HIF, which coordinates the interdependent processes of iron mobilization and erythropoietin (EPO) production to increase RBC production and, ultimately, improve oxygen delivery. As a HIF stabilizer with ...
TABLE-US-00008 TABLE VIII No. R5 R L 265 --H 2-fluorophenyl --C(CH3)2-- 266 --H 3-fluorophenyl --C(CH3)2-- 267 --H 4-fluorophenyl --C(CH3)2-- 268 --H 2-chlorophenyl --C(CH3)2-- 269 --H 3-chlorophenyl --C(CH3)2-- 270 --H 4-chlorophenyl --C(CH3)2-- 271 --H 2-methylphenyl --C(CH3)2-- 272 --H 3-methylphenyl --C(CH3)2-- 273 --H 4-methylphenyl --C(CH3)2-- 274 --CH3 2-fluorophenyl --C(CH3)2-- 275 --CH3 3-fluorophenyl --C(CH3)2-- 276 --CH3 4-fluorophenyl --C(CH3)2-- 277 --CH3 2-chlorophenyl --C(CH3)2-- 278 --CH3 3-chlorophenyl --C(CH3)2-- 279 --CH3 4-chlorophenyl --C(CH3)2-- 280 --CH3 2-methylphenyl --C(CH3)2-- 281 --CH3 3-methylphenyl --C(CH3)2-- 282 --CH3 4-methylphenyl --C(CH3)2-- 283 --CH2CH3 2-fluorophenyl --C(CH3)2-- 284 --CH2CH3 3-fluorophenyl --C(CH3)2-- 285 --CH2CH3 4-fluorophenyl --C(CH3)2-- 286 --CH2CH3 2-chlorophenyl --C(CH3)2-- 287 --CH2CH3 3-chlorophenyl --C(CH3)2-- 288 --CH2CH3 4-chlorophenyl --C(CH3)2-- 289 --CH2CH3 2-methylphenyl --C(CH3)2-- 290 --CH2CH3 3-methylphenyl --C(CH3)2-- 291 ...
Cytochrome P450 omega hydroxylases, also termed cytochrome P450 ω-hydroxylases, CYP450 omega hydroxylases, CYP450 ω-hydroxylases, CYP omega hydroxylase, CYP ω-hydroxylases, fatty acid omega hydroxylases, cytochrome P450 monooxygenases, and fatty acid monooxygenases, are a set of cytochrome P450-containing enzymes that catalyze the addition of a hydroxyl residue to a fatty acid Substrate (chemistry). The CYP omega hydroxylases are often referred to as monoxygenases; however, the monooxygenases are CYP450 enzymes that add a hydroxyl group to a wide range of xenobiotic (e.g. drugs, industrial toxins) and naturally occurring endobiotic (e.g. cholesterol) substrates, most of which are not fatty acids. The CYP450 omega hydroxylases are accordingly better viewed as a subset of monooxygenases that have the ability to hydroxylate fatty acids. While once regarded as functioning mainly in the catabolism of dietary fatty acids, the omega oxygenases are now considered critical in the production or ...
EGLN1_HUMAN] Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates a specific proline found in each of the oxygen-dependent degradation (ODD) domains (N-terminal, NODD, and C-terminal, CODD) of HIF1A. Also hydroxylates HIF2A. Has a preference for the CODD site for both HIF1A and HIF1B. Hydroxylated HIFs are then targeted for proteasomal degradation via the von Hippel-Lindau ubiquitination complex. Under hypoxic conditions, the hydroxylation reaction is attenuated allowing HIFs to escape degradation resulting in their translocation to the nucleus, heterodimerization with HIF1B, and increased expression of hypoxy-inducible genes. EGLN1 is the most important isozyme under normoxia and, through regulating the stability of HIF1, involved in various hypoxia-influenced processes such as angiogenesis in retinal and cardiac functionality.[3] [4] [5] [6] [7] ...
Metazoans rely on aerobic energy production, which requires an adequate oxygen supply. During reduced oxygen supply (hypoxia), the most profound changes in gene expression are mediated by transcription factors known as hypoxia-inducible factors (HIFs). HIF alpha proteins are commonly posttranslationally regulated by prolyl-4-hydroxylase (PHD) enzymes, which are direct "sensors" of cellular oxygen levels. We examined the molecular evolution of the metazoan PHD-HIF oxygen-sensing system by constructing complete phylogenies for PHD and HIF alpha genes and used computational tools to characterize the molecular changes underlying the functional divergence of PHD and HIF alpha duplicates. The presence of PHDs in metazoan genomes predates the emergence of HIF alphas. Our analysis revealed an unexpected diversity of PHD genes and HIF alpha sequence characteristics in invertebrates, suggesting that the simple oxygen-sensing systems of Caenorhabditis and Drosophila may not be typical of other invertebrate ...
Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that functions as a master regulator of oxygen homeostasis. It consists of two subunits: an inducibly-expressed HIF-1alpha subunit and a constitutively-expressed HIF-1beta subunit. Under normoxia, HIF-1 alpha undergoes hydroxylation at specific prolyl residues which leads to an immediate ubiquitination and subsequent proteasomal degradation of the subunit. In contrast, under hypoxia, HIF-1 alpha subunit becomes stable and interacts with coactivators such as p300/CBP to modulate its transcriptional activity. Eventually, HIF-1 acts as a master regulator of numerous hypoxia-inducible genes under hypoxic conditions. The target genes of HIF-1 encode proteins that increase O2 delivery and mediate adaptive responses to O2 deprivation. Despite its name, HIF-1 is induced not only in response to reduced oxygen availability but also by other stimulants, such as nitric oxide, or various growth factors ...
Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that functions as a master regulator of oxygen homeostasis. It consists of two subunits: an inducibly-expressed HIF-1alpha subunit and a constitutively-expressed HIF-1beta subunit. Under normoxia, HIF-1 alpha undergoes hydroxylation at specific prolyl residues which leads to an immediate ubiquitination and subsequent proteasomal degradation of the subunit. In contrast, under hypoxia, HIF-1 alpha subunit becomes stable and interacts with coactivators such as p300/CBP to modulate its transcriptional activity. Eventually, HIF-1 acts as a master regulator of numerous hypoxia-inducible genes under hypoxic conditions. The target genes of HIF-1 encode proteins that increase O2 delivery and mediate adaptive responses to O2 deprivation. Despite its name, HIF-1 is induced not only in response to reduced oxygen availability but also by other stimulants, such as nitric oxide, or various growth factors ...
Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that functions as a master regulator of oxygen homeostasis. It consists of two subunits: an inducibly-expressed HIF-1alpha subunit and a constitutively-expressed HIF-1beta subunit. Under normoxia, HIF-1 alpha undergoes hydroxylation at specific prolyl residues which leads to an immediate ubiquitination and subsequent proteasomal degradation of the subunit. In contrast, under hypoxia, HIF-1 alpha subunit becomes stable and interacts with coactivators such as p300/CBP to modulate its transcriptional activity. Eventually, HIF-1 acts as a master regulator of numerous hypoxia-inducible genes under hypoxic conditions. The target genes of HIF-1 encode proteins that increase O2 delivery and mediate adaptive responses to O2 deprivation. Despite its name, HIF-1 is induced not only in response to reduced oxygen availability but also by other stimulants, such as nitric oxide, or various growth factors ...