Genomes and Genes
procollagen proline dioxygenase
Summary: A mixed-function oxygenase that catalyzes the hydroxylation of a prolyl-glycyl containing peptide, usually in PROTOCOLLAGEN, to a hydroxyprolylglycyl-containing-peptide. The enzyme utilizes molecular OXYGEN with a concomitant oxidative decarboxylation of 2-oxoglutarate to SUCCINATE. The enzyme occurs as a tetramer of two alpha and two beta subunits. The beta subunit of procollagen-proline dioxygenase is identical to the enzyme PROTEIN DISULFIDE-ISOMERASES.
- Asikainen T, Ahmad A, Schneider B, Ho W, Arend M, Brenner M, et al. Stimulation of HIF-1alpha, HIF-2alpha, and VEGF by prolyl 4-hydroxylase inhibition in human lung endothelial and epithelial cells. Free Radic Biol Med. 2005;38:1002-13 pubmed
- Yuan G, Nanduri J, Khan S, Semenza G, Prabhakar N. Induction of HIF-1alpha expression by intermittent hypoxia: involvement of NADPH oxidase, Ca2+ signaling, prolyl hydroxylases, and mTOR. J Cell Physiol. 2008;217:674-85 pubmed publisher..Rapamycin or cycloheximide, blocked increased HIF-1alpha levels during re-oxygenation indicating that mTOR-dependent protein synthesis is required for the persistent elevation of HIF-1alpha levels during re-oxygenation. ..
- McMahon S, Charbonneau M, Grandmont S, Richard D, Dubois C. Transforming growth factor beta1 induces hypoxia-inducible factor-1 stabilization through selective inhibition of PHD2 expression. J Biol Chem. 2006;281:24171-81 pubmed..This study reveals a novel mechanism by which a growth factor controls HIF-1 stability, and thereby drives the expression of specific genes, through the regulation of PHD2 levels. ..
- Koski M, Hieta R, Hirsilä M, Rönkä A, Myllyharju J, Wierenga R. The crystal structure of an algal prolyl 4-hydroxylase complexed with a proline-rich peptide reveals a novel buried tripeptide binding motif. J Biol Chem. 2009;284:25290-301 pubmed publisher..The importance of these findings for understanding the specific binding and hydroxylation of (X-Pro-Gly)(n) sequences by collagen P4Hs is also discussed. ..
- Wu S, Nishiyama N, Kano M, Morishita Y, Miyazono K, Itaka K, et al. Enhancement of angiogenesis through stabilization of hypoxia-inducible factor-1 by silencing prolyl hydroxylase domain-2 gene. Mol Ther. 2008;16:1227-34 pubmed publisher..In the light of these findings, PHD2 silencing by RNAi might offer a potential tool for angiogenic therapy. ..
- Rohrbach S, Simm A, Pregla R, Franke C, Katschinski D. Age-dependent increase of prolyl-4-hydroxylase domain (PHD) 3 expression in human and mouse heart. Biogerontology. 2005;6:165-71 pubmed..These data may explain the previously reported reduction of HIF-1alpha and HIF-1 target genes such as the vascular endothelial growth factor in ageing tissue. ..
- Hirsilä M, Koivunen P, Xu L, Seeley T, Kivirikko K, Myllyharju J. Effect of desferrioxamine and metals on the hydroxylases in the oxygen sensing pathway. FASEB J. 2005;19:1308-10 pubmed..The effective inhibition of FIH by these metals and zinc probably leads to full transcriptional activity of HIF-alpha even in concentrations that produce no stabilization of HIF-alpha. ..
- Siddiq A, Ayoub I, Chavez J, Aminova L, Shah S, Lamanna J, et al. Hypoxia-inducible factor prolyl 4-hydroxylase inhibition. A target for neuroprotection in the central nervous system. J Biol Chem. 2005;280:41732-43 pubmed..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. ..
- Minamishima Y, Moslehi J, Bardeesy N, Cullen D, Bronson R, Kaelin W. Somatic inactivation of the PHD2 prolyl hydroxylase causes polycythemia and congestive heart failure. Blood. 2008;111:3236-44 pubmed..The latter is likely the result of hyperviscosity syndrome and volume overload, although a direct effect of chronic, high-level HIF stimulation on cardiac myocytes cannot be excluded. ..
- Mazzone M, Dettori D, de Oliveira R, Loges S, Schmidt T, Jonckx B, et al. Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. Cell. 2009;136:839-851 pubmed publisher..Inhibition of PHD2 may offer alternative therapeutic opportunities for anticancer therapy. ..
- Hoffart L, Barr E, Guyer R, Bollinger J, Krebs C. Direct spectroscopic detection of a C-H-cleaving high-spin Fe(IV) complex in a prolyl-4-hydroxylase. Proc Natl Acad Sci U S A. 2006;103:14738-43 pubmed..The close correspondence of the accumulating states in the P4H and TauD reactions supports the hypothesis of a conserved mechanism for substrate hydroxylation by enzymes in this family. ..
- Appelhoff R, Tian Y, Raval R, Turley H, Harris A, Pugh C, et al. Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor. J Biol Chem. 2004;279:38458-65 pubmed
- Wang J, Pantopoulos K. The pathway for IRP2 degradation involving 2-oxoglutarate-dependent oxygenase(s) does not require the E3 ubiquitin ligase activity of pVHL. Biochim Biophys Acta. 2005;1743:79-85 pubmed..However, the iron-dependent degradation of endogenous IRP2 is not impaired in VHL-deficient cell lines, suggesting that pVHL is not a necessary component of this pathway. ..
- Cabral W, Chang W, Barnes A, Weis M, Scott M, Leikin S, et al. Prolyl 3-hydroxylase 1 deficiency causes a recessive metabolic bone disorder resembling lethal/severe osteogenesis imperfecta. Nat Genet. 2007;39:359-65 pubmed..Proband collagen secretion was moderately delayed, but total collagen secretion was increased. Prolyl 3-hydroxylase 1 is therefore crucial for bone development and collagen helix formation...
- Barth S, Nesper J, Hasgall P, Wirthner R, Nytko K, Edlich F, et al. The peptidyl prolyl cis/trans isomerase FKBP38 determines hypoxia-inducible transcription factor prolyl-4-hydroxylase PHD2 protein stability. Mol Cell Biol. 2007;27:3758-68 pubmed..Downregulation of FKBP38 did not affect PHD2 mRNA levels but prolonged PHD2 protein stability, suggesting that FKBP38 is involved in PHD2 protein regulation. ..
- Kersteen E, Higgin J, Raines R. Production of human prolyl 4-hydroxylase in Escherichia coli. Protein Expr Purif. 2004;38:279-91 pubmed..2 mg/g of cell paste). We also report a direct, automated assay of proline hydroxylation using high-performance liquid chromatography. We anticipate that these advances will facilitate structure-function analyses of P4H. ..
- Berchner Pfannschmidt U, Tug S, Trinidad B, Oehme F, Yamac H, Wotzlaw C, et al. Nuclear oxygen sensing: induction of endogenous prolyl-hydroxylase 2 activity by hypoxia and nitric oxide. J Biol Chem. 2008;283:31745-53 pubmed publisher..Our data suggest a role for PHD2 as a decisive oxygen sensor of the hypoxia-inducible factor degradation pathway within the cell nucleus. ..
- Ehrismann D, Flashman E, Genn D, Mathioudakis N, Hewitson K, Ratcliffe P, et al. Studies on the activity of the hypoxia-inducible-factor hydroxylases using an oxygen consumption assay. Biochem J. 2007;401:227-34 pubmed
- Nakayama K, Gazdoiu S, Abraham R, Pan Z, RONAI Z. Hypoxia-induced assembly of prolyl hydroxylase PHD3 into complexes: implications for its activity and susceptibility for degradation by the E3 ligase Siah2. Biochem J. 2007;401:217-26 pubmed..These findings provide new insight into the mechanism underlying the regulation of PHD3 availability and activity in hypoxia by the E3 ligase Siah2. ..
- Myllyharju J. Prolyl 4-hydroxylases, key enzymes in the synthesis of collagens and regulation of the response to hypoxia, and their roles as treatment targets. Ann Med. 2008;40:402-17 pubmed publisher..Studies with P4H inhibitors in various animal models of fibrosis, anemia, and ischemia and ongoing clinical trials with HIF-P4H inhibitors support this hypothesis by demonstrating efficacy in many applications. ..
- Villar D, Vara Vega A, Landazuri M, del Peso L. Identification of a region on hypoxia-inducible-factor prolyl 4-hydroxylases that determines their specificity for the oxygen degradation domains. Biochem J. 2007;408:231-40 pubmed..Importantly, mapping of these sequences on the EGLN1 tertiary structure indicates that substrate specificity is determined by a region relatively remote from the catalytic site. ..
- Neubauer A, Soini J, Bollok M, Zenker M, Sandqvist J, Myllyharju J, et al. Fermentation process for tetrameric human collagen prolyl 4-hydroxylase in Escherichia coli: improvement by gene optimisation of the PDI/beta subunit and repeated addition of the inducer anhydrotetracycline. J Biotechnol. 2007;128:308-21 pubmed..The optimisation approach resulted in a fermentation yield of 143 mg L(-1) of active C-P4H, corresponding to approximately 7.5% of the total soluble cell protein. ..
- Percy M, Zhao Q, Flores A, Harrison C, Lappin T, Maxwell P, et al. A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis. Proc Natl Acad Sci U S A. 2006;103:654-9 pubmed..Our findings indicate that PHD2 is critical for normal regulation of HIF in humans. ..
- Selak M, Armour S, MacKenzie E, Boulahbel H, Watson D, Mansfield K, et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell. 2005;7:77-85 pubmed..These results suggest a mechanistic link between SDH mutations and HIF-1alpha induction, providing an explanation for the highly vascular tumors that develop in the absence of VHL mutations. ..
- Berchner Pfannschmidt U, Yamac H, Trinidad B, Fandrey J. Nitric oxide modulates oxygen sensing by hypoxia-inducible factor 1-dependent induction of prolyl hydroxylase 2. J Biol Chem. 2007;282:1788-96 pubmed..In conclusion, we identified the induction of PHD2 as an underlying mechanism of NO-induced degradation of HIF-1alpha. ..
- Fong G, Takeda K. Role and regulation of prolyl hydroxylase domain proteins. Cell Death Differ. 2008;15:635-41 pubmed publisher..Future investigations are needed to explore in vivo specificity of PHDs over different HIF-alpha subunits and differential roles of PHD isoforms in different biological processes. ..
- Semenza G. Hypoxia-inducible factor 1 (HIF-1) pathway. Sci STKE. 2007;2007:cm8 pubmed..A growing number of proteins and small molecules have been identified that regulate HIF-1 activity by modulating the physical or functional interaction of PHD2, VHL, FIH-1, RACK1, or HSP90 with HIF-1alpha. ..
- Marxsen J, Stengel P, Doege K, Heikkinen P, Jokilehto T, Wagner T, et al. Hypoxia-inducible factor-1 (HIF-1) promotes its degradation by induction of HIF-alpha-prolyl-4-hydroxylases. Biochem J. 2004;381:761-7 pubmed..We propose a direct, negative regulatory mechanism, which limits accumulation of HIF-1alpha in hypoxia and leads to accelerated degradation on reoxygenation after long-term hypoxia. ..
- Metzen E, Zhou J, Jelkmann W, Fandrey J, Brüne B. Nitric oxide impairs normoxic degradation of HIF-1alpha by inhibition of prolyl hydroxylases. Mol Biol Cell. 2003;14:3470-81 pubmed..We conclude that GSNO-attenuated prolyl hydroxylase activity accounts for HIF-1alpha accumulation under conditions of NO formation during normoxia and that PHD activity is subject to regulation by NO. ..
- Holster T, Pakkanen O, Soininen R, Sormunen R, Nokelainen M, Kivirikko K, et al. Loss of assembly of the main basement membrane collagen, type IV, but not fibril-forming collagens and embryonic death in collagen prolyl 4-hydroxylase I null mice. J Biol Chem. 2007;282:2512-9 pubmed..The primary cause of death of the null embryos was thus most likely an abnormal assembly of collagen IV. ..
- Knowles H, Tian Y, Mole D, Harris A. Novel mechanism of action for hydralazine: induction of hypoxia-inducible factor-1alpha, vascular endothelial growth factor, and angiogenesis by inhibition of prolyl hydroxylases. Circ Res. 2004;95:162-9 pubmed..This represents a novel mechanism of action for hydralazine and presents HIF as a potential target for treatment of ischemic disease. ..
- To K, Huang L. Suppression of hypoxia-inducible factor 1alpha (HIF-1alpha) transcriptional activity by the HIF prolyl hydroxylase EGLN1. J Biol Chem. 2005;280:38102-7 pubmed..Our finding also provided new insight into the pharmacological manipulation of the HIF prolyl hydroxylase for ischemic diseases. ..
- Soilleux E, Turley H, Tian Y, Pugh C, Gatter K, Harris A. Use of novel monoclonal antibodies to determine the expression and distribution of the hypoxia regulatory factors PHD-1, PHD-2, PHD-3 and FIH in normal and neoplastic human tissues. Histopathology. 2005;47:602-10 pubmed..These monoclonal antibodies will allow further larger scale studies to determine the significance of PHD and FIH expression in neoplasia. ..
- Lee S, Nakamura E, Yang H, Wei W, Linggi M, Sajan M, et al. Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial pheochromocytoma genes: developmental culling and cancer. Cancer Cell. 2005;8:155-67 pubmed..Moreover, EglN3 proapoptotic activity requires SDH activity because EglN3 is feedback inhibited by succinate. These studies suggest that failure of developmental apoptosis plays a role in pheochromocytoma pathogenesis. ..
- Andersson Sjöland A, de Alba C, Nihlberg K, Becerril C, Ramirez R, Pardo A, et al. Fibrocytes are a potential source of lung fibroblasts in idiopathic pulmonary fibrosis. Int J Biochem Cell Biol. 2008;40:2129-40 pubmed publisher..41; p<0.04). These findings indicate that circulating fibrocytes, likely recruited through the CXCR4/CXCL12 axis, may contribute to the expansion of the fibroblast/myofibroblast population in idiopathic pulmonary fibrosis. ..
- Centanin L, Dekanty A, Romero N, Irisarri M, Gorr T, Wappner P. Cell autonomy of HIF effects in Drosophila: tracheal cells sense hypoxia and induce terminal branch sprouting. Dev Cell. 2008;14:547-58 pubmed publisher..We propose that the autonomous response to hypoxia that occurs in tracheal cells enhances tracheal sensitivity to increasing Branchless levels, and that this mechanism is a cardinal step in hypoxia-dependent tracheal sprouting. ..
- Gorres K, Raines R. Direct and continuous assay for prolyl 4-hydroxylase. Anal Biochem. 2009;386:181-5 pubmed publisher..Thus, the assay described herein could facilitate biochemical analyses of this essential enzyme. ..
- Couvelard A, Deschamps L, Rebours V, Sauvanet A, Gatter K, Pezzella F, et al. Overexpression of the oxygen sensors PHD-1, PHD-2, PHD-3, and FIH Is associated with tumor aggressiveness in pancreatic endocrine tumors. Clin Cancer Res. 2008;14:6634-9 pubmed publisher..These molecules that play an important role in the control of hypoxia-induced genes may have a function in the regulation of cellular proliferation and differentiation during endocrine tumorigenesis. ..
- Kato H, Inoue T, Asanoma K, Nishimura C, Matsuda T, Wake N. Induction of human endometrial cancer cell senescence through modulation of HIF-1alpha activity by EGLN1. Int J Cancer. 2006;118:1144-53 pubmed..These results also suggested the availability of negative regulation of HIF-1 signals for uterine cancer treatment, especially for uterine sarcomas that have worse prognosis and show a high frequency of EGLN1 gene abnormality. ..
- Li D, Hirsilä M, Koivunen P, Brenner M, Xu L, Yang C, et al. Many amino acid substitutions in a hypoxia-inducible transcription factor (HIF)-1alpha-like peptide cause only minor changes in its hydroxylation by the HIF prolyl 4-hydroxylases: substitution of 3,4-dehydroproline or azetidine-2-carboxylic acid for . J Biol Chem. 2004;279:55051-9 pubmed..The data obtained for the three HIF-P4Hs in various experiments were in most cases similar, but in some cases HIF-P4H-3 showed distinctly different properties. ..
- Wirthner R, Balamurugan K, Stiehl D, Barth S, Spielmann P, Oehme F, et al. Determination and modulation of prolyl-4-hydroxylase domain oxygen sensor activity. Methods Enzymol. 2007;435:43-60 pubmed..We provide a detailed description of the expression and purification of the PHDs as well as of an HIF-alpha-dependent and a HIF-alpha-independent PHD assay. ..
- Neubauer A, Neubauer P, Myllyharju J. High-level production of human collagen prolyl 4-hydroxylase in Escherichia coli. Matrix Biol. 2005;24:59-68 pubmed..The enzyme expressed in E. coli differed from those present in vivo and those produced in other hosts in that it lacked the N glycosylation of its alpha subunits, which may be advantageous in crystallization experiments. ..
- Kaelin W, Ratcliffe P. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell. 2008;30:393-402 pubmed publisher..HIF affects signaling pathways that influence development, metabolism, inflammation, and integrative physiology. Accordingly, HIF-modulatory drugs are now being developed for diverse diseases. ..
- Lee K, Lynd J, O Reilly S, Kiupel M, McCormick J, LaPres J. The biphasic role of the hypoxia-inducible factor prolyl-4-hydroxylase, PHD2, in modulating tumor-forming potential. Mol Cancer Res. 2008;6:829-42 pubmed publisher..These findings support a biphasic model for the relationship between PHD2 activity and malignant transformation. ..
- Nakayama K, Frew I, Hagensen M, Skals M, Habelhah H, Bhoumik A, et al. Siah2 regulates stability of prolyl-hydroxylases, controls HIF1alpha abundance, and modulates physiological responses to hypoxia. Cell. 2004;117:941-52 pubmed..Thus, the control of PHD1/3 by Siah1a/2 constitutes another level of complexity in the regulation of HIF1alpha during hypoxia. ..
- Ozer A, Wu L, Bruick R. The candidate tumor suppressor ING4 represses activation of the hypoxia inducible factor (HIF). Proc Natl Acad Sci U S A. 2005;102:7481-6 pubmed..These data support a model in which, in addition to regulating HIF stability, HIF prolyl hydroxylases can modulate HIF function through the recruitment of ING4, a likely component of a chromatin-remodeling complex. ..
- Fähling M, Mrowka R, Steege A, Nebrich G, Perlewitz A, Persson P, et al. Translational control of collagen prolyl 4-hydroxylase-alpha(I) gene expression under hypoxia. J Biol Chem. 2006;281:26089-101 pubmed..Thus, the alteration of translational efficiency by nucleolin, which occurs through a hypoxia inducible factor independent pathway, is an important step in C-P4H-alpha(I) regulation under hypoxia. ..
- Lomb D, Straub J, Freeman R. Prolyl hydroxylase inhibitors delay neuronal cell death caused by trophic factor deprivation. J Neurochem. 2007;103:1897-906 pubmed..Thus, while HIF prolyl hydroxylase inhibitors can delay cell death in NGF-deprived neurons, they do so through distinct mechanisms that, at least in the case of DHB, are partly independent of HIF stabilization. ..
- Choi K, Lee T, Lee N, Kim J, Yang E, Yoon J, et al. Inhibition of the catalytic activity of hypoxia-inducible factor-1alpha-prolyl-hydroxylase 2 by a MYND-type zinc finger. Mol Pharmacol. 2005;68:1803-9 pubmed
- Aragones J, Schneider M, van Geyte K, Fraisl P, Dresselaers T, Mazzone M, et al. Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism. Nat Genet. 2008;40:170-80 pubmed publisher..These findings delineate a new role of Phd1 in hypoxia tolerance and offer new treatment perspectives for disorders characterized by oxidative stress. ..
- Ladroue C, Carcenac R, Leporrier M, Gad S, Le Hello C, Galateau Salle F, et al. PHD2 mutation and congenital erythrocytosis with paraganglioma. N Engl J Med. 2008;359:2685-92 pubmed publisher..This mutation affects PHD2 function and stabilizes HIF-alpha proteins. In addition, we demonstrate loss of heterozygosity of PHD2 in the tumor, suggesting that PHD2 could be a tumor-suppressor gene. ..
- Arquier N, Vigne P, Duplan E, Hsu T, Therond P, Frelin C, et al. Analysis of the hypoxia-sensing pathway in Drosophila melanogaster. Biochem J. 2006;393:471-80 pubmed..Hypoxic stabilization of ODD-GFP in the ectoderm was restored by inducing VHL expression in these cells. These results show that Drosophila tissues exhibit different sensitivities to hypoxia. ..
- Percy M. Genetically heterogeneous origins of idiopathic erythrocytosis. Hematology. 2007;12:131-9 pubmed..Studying the molecular basis of IE will provide insights into the control of Epo synthesis and Epo-induced signaling pathways. ..