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Procollagen-proline dioxygenase

January 01, 1970

Procollagen-proline dioxygenase, commonly known as prolyl hydroxylase, is a member of the class of enzymes known as alpha-ketoglutarate-dependent hydroxylases. These enzymes catalyze the incorporation of oxygen into organic substrates through a mechanism that requires alpha-Ketoglutaric acid, Fe2+, and ascorbate.[1][2] This particular enzyme catalyzes the formation of (2S, 4R)-4-hydroxyproline, a compound that represents the most prevalent post-translational modification in the human proteome.[3]

Procollagen-proline dioxygenase
Alpha subunits of procollagen-proline dioxygenase. Image shows substrate binding region (orange) and the binding groove of tyrosine residues (yellow)
Identifiers
EC no.1.14.11.2
CAS no.9028-06-2
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Search
PMCarticles
PubMedarticles
NCBIproteins

Enzyme mechanism edit

Procollagen-proline dioxygenase catalyzes the following reaction:

L-proline + alpha-ketoglutaric acid + O2 → (2S, 4R)-4-hydroxyproline + succinate + CO2

The mechanism for the reaction is similar to that of other dioxygenases, and occurs in two distinct stages:[3] In the first, a highly reactive Fe(IV)=O species is produced. Molecular oxygen is bound end-on in an axial position, producing a dioxygen unit. Nucleophilic attack on C2 generates a tetrahedral intermediate, with loss of the double bond in the dioxygen unit and bonds to iron and the alpha carbon of 2-oxoglutarate. Subsequent elimination of CO2 coincides with the formation of the Fe(IV)=O species. The second stage involves the abstraction of the pro-R hydrogen atom from C-4 of the proline substrate followed by radical combination, which yields hydroxyproline.[4]

As a consequence of the reaction mechanism, one molecule of 2-oxoglutarate is decarboxylated, forming succinate. This succinate is hydrolyzed and replaced with another 2-oxoglutarate after each reaction, and it has been concluded that in the presence of 2-oxoglutarate, enzyme-bound Fe2+ is rapidly converted to Fe3+, leading to inactivation of the enzyme.[5] Ascorbate is utilized as a cofactor to reduce Fe3+ back to Fe2+.[6]

Enzyme structure edit

 
A closer view of the substrate binding domain of prolyl hydroxylase. Tyrosine residues, which form the binding groove, are displayed in yellow.

Prolyl hydroxylase is a tetramer with 2 unique subunits.[7] The α subunit is 59 kDa and is responsible for both peptide binding and for catalytic activity.[8] The peptide binding domain spans residues 140-215 of the α subunit,[9] and consists of a concave surface lined with multiple tyrosine residues which interact favorably with the proline-rich substrate. The active site consists of Fe2+ bound to two histidine residues and one aspartate residue, a characteristic shared by most 2-oxoglutarate-dependent dioxygenases. The 55 kDa β subunit is responsible for the enzyme’s localization to and retention in the endoplasmic reticulum.[10] This subunit is identical to the enzyme known as protein disulfide isomerase.[11]

Biological function edit

Prolyl hydroxylase catalyzes the formation of hydroxyproline. The modification has a significant impact on the stability of collagen, the major connective tissue of the human body.[12] Specifically, hydroxylation increases the melting temperature (Tm) of helical collagen by 16 °C, as compared to unhydroxylated collagen,[13] a difference that allows the protein to be stable at body temperature. Due to the abundance of collagen (about one third of total protein) in humans, and the high occurrence of this modification in collagen, hydroxyproline is quantitatively the most abundant post-translational modification in humans.[14]

The enzyme acts specifically on proline contained within the X-Pro-Gly motif – where Pro is proline. Because of this motif-specific behavior, the enzyme also acts on other proteins that contain this same sequence. Such proteins include C1q,[15] elastins,[16] PrP,[17] Argonaute 2,[18] and conotoxins,[19] among others.

Disease relevance edit

As prolyl hydroxylase requires ascorbate as a cofactor to function,[5] its absence compromises the enzyme’s activity. The resulting decreased hydroxylation leads to the disease condition known as scurvy. Since stability of collagen is compromised in scurvy patients, symptoms include weakening of blood vessels causing purpura, petechiae, and gingival bleeding.

Hypoxia-inducible factor (HIF) is an evolutionarily conserved transcription factor[20] that allows the cell to respond physiologically to decreases in oxygen.[21] A class of prolyl hydroxylases which act specifically on HIF has been identified;[22] hydroxylation of HIF allows the protein to be targeted for degradation.[22] HIF prolyl-hydroxylase has been targeted by a variety of inhibitors that aim to treat stroke,[23] kidney disease,[24] ischemia,[25] anemia,[26] and other important diseases.

Alternate names edit

  • Protocollagen hydroxylase
  • Prolyl hydroxylase
  • Prolyl 4-hydroxylase
  • Protocollagen prolyl hydroxylase

References edit

  1. ^ Smith TG, Talbot NP (April 2010). "Prolyl hydroxylases and therapeutics". Antioxidants & Redox Signaling. 12 (4): 431–3. doi:10.1089/ars.2009.2901. PMID 19761407.
  2. ^ Hutton JJ, Trappel AL, Udenfriend S (July 1966). "Requirements for alpha-ketoglutarate, ferrous ion and ascorbate by collagen proline hydroxylase". Biochemical and Biophysical Research Communications. 24 (2): 179–84. doi:10.1016/0006-291x(66)90716-9. PMID 5965224.
  3. ^ a b Gorres KL, Raines RT (April 2010). "Prolyl 4-hydroxylase". Critical Reviews in Biochemistry and Molecular Biology. 45 (2): 106–24. doi:10.3109/10409231003627991. PMC 2841224. PMID 20199358.
  4. ^ Fujita Y, Gottlieb A, Peterkofsky B, Udenfriend S, Witkop B (1964). "The Preparation of cis- and trans-4-H3-L-Prolines and Their Use in Studying the Mechanism of Enzymatic Hydroxylation in Chick Embryos". Journal of the American Chemical Society. 86 (21): 4709–4716. doi:10.1021/ja01075a036.
  5. ^ a b de Jong L, Albracht SP, Kemp A (June 1982). "Prolyl 4-hydroxylase activity in relation to the oxidation state of enzyme-bound iron. The role of ascorbate in peptidyl proline hydroxylation". Biochimica et Biophysica Acta. 704 (2): 326–32. doi:10.1016/0167-4838(82)90162-5. PMID 6285984.
  6. ^ De Jong L, Kemp A (May 1984). "Stoicheiometry and kinetics of the prolyl 4-hydroxylase partial reaction". Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology. 787 (1): 105–11. doi:10.1016/0167-4838(84)90113-4. PMID 6326839.
  7. ^ Berg RA, Prockop DJ (February 1973). "Affinity column purification of protocollagen proline hydroxylase from chick embryos and further characterization of the enzyme". The Journal of Biological Chemistry. 248 (4): 1175–82. doi:10.1016/S0021-9258(19)44278-6. PMID 4346946.
  8. ^ Helaakoski T, Vuori K, Myllylä R, Kivirikko KI, Pihlajaniemi T (June 1989). "Molecular cloning of the alpha-subunit of human prolyl 4-hydroxylase: the complete cDNA-derived amino acid sequence and evidence for alternative splicing of RNA transcripts". Proceedings of the National Academy of Sciences of the United States of America. 86 (12): 4392–6. Bibcode:1989PNAS...86.4392H. doi:10.1073/pnas.86.12.4392. PMC 287275. PMID 2543975.
  9. ^ Pekkala M, Hieta R, Bergmann U, Kivirikko KI, Wierenga RK, Myllyharju J (December 2004). "The peptide-substrate-binding domain of collagen prolyl 4-hydroxylases is a tetratricopeptide repeat domain with functional aromatic residues". The Journal of Biological Chemistry. 279 (50): 52255–61. doi:10.1074/jbc.M410007200. PMID 15456751.
  10. ^ Vuori K, Pihlajaniemi T, Myllylä R, Kivirikko KI (November 1992). "Site-directed mutagenesis of human protein disulphide isomerase: effect on the assembly, activity and endoplasmic reticulum retention of human prolyl 4-hydroxylase in Spodoptera frugiperda insect cells". The EMBO Journal. 11 (11): 4213–7. doi:10.1002/j.1460-2075.1992.tb05515.x. PMC 556932. PMID 1327760.
  11. ^ Pihlajaniemi T, Helaakoski T, Tasanen K, Myllylä R, Huhtala ML, Koivu J, Kivirikko KI (March 1987). "Molecular cloning of the beta-subunit of human prolyl 4-hydroxylase. This subunit and protein disulphide isomerase are products of the same gene". The EMBO Journal. 6 (3): 643–9. doi:10.1002/j.1460-2075.1987.tb04803.x. PMC 553446. PMID 3034602.
  12. ^ Shoulders MD, Raines RT (2009). "Collagen structure and stability". Annual Review of Biochemistry. 78: 929–58. doi:10.1146/annurev.biochem.77.032207.120833. PMC 2846778. PMID 19344236.
  13. ^ Berg RA, Prockop DJ (May 1973). "The thermal transition of a non-hydroxylated form of collagen. Evidence for a role for hydroxyproline in stabilizing the triple-helix of collagen". Biochemical and Biophysical Research Communications. 52 (1): 115–20. doi:10.1016/0006-291x(73)90961-3. PMID 4712181.
  14. ^ Gorres, Kelly L.; Raines, Ronald T. (April 2010). "Prolyl 4-hydroxylase". Critical Reviews in Biochemistry and Molecular Biology. 45 (2): 106–124. doi:10.3109/10409231003627991. PMC 2841224. PMID 20199358.
  15. ^ Müller W, Hanauske-Abel H, Loos M (October 1978). "Biosynthesis of the first component of complement by human and guinea pig peritoneal macrophages: evidence for an independent production of the C1 subunits". Journal of Immunology. 121 (4): 1578–84. doi:10.4049/jimmunol.121.4.1578. PMID 701808. S2CID 36397927.
  16. ^ Rosenbloom J, Cywinski A (June 1976). "Inhibition of proline hydroxylation does not inhibit secretion of tropoelastin by chick aorta cells". FEBS Letters. 65 (2): 246–50. doi:10.1016/0014-5793(76)80490-5. PMID 6335. S2CID 34210226.
  17. ^ Gill AC, Ritchie MA, Hunt LG, Steane SE, Davies KG, Bocking SP, Rhie AG, Bennett AD, Hope J (October 2000). "Post-translational hydroxylation at the N-terminus of the prion protein reveals presence of PPII structure in vivo". The EMBO Journal. 19 (20): 5324–31. doi:10.1093/emboj/19.20.5324. PMC 314005. PMID 11032800.
  18. ^ Qi HH, Ongusaha PP, Myllyharju J, Cheng D, Pakkanen O, Shi Y, Lee SW, Peng J, Shi Y (September 2008). "Prolyl 4-hydroxylation regulates Argonaute 2 stability". Nature. 455 (7211): 421–4. Bibcode:2008Natur.455..421Q. doi:10.1038/nature07186. PMC 2661850. PMID 18690212.
  19. ^ Daly NL, Craik DJ (February 2009). "Structural studies of conotoxins". IUBMB Life. 61 (2): 144–50. doi:10.1002/iub.158. PMID 19165896. S2CID 8678009.
  20. ^ Bacon NC, Wappner P, O'Rourke JF, Bartlett SM, Shilo B, Pugh CW, Ratcliffe PJ (August 1998). "Regulation of the Drosophila bHLH-PAS protein Sima by hypoxia: functional evidence for homology with mammalian HIF-1 alpha". Biochemical and Biophysical Research Communications. 249 (3): 811–6. doi:10.1006/bbrc.1998.9234. PMID 9731218.
  21. ^ Smith TG, Robbins PA, Ratcliffe PJ (May 2008). "The human side of hypoxia-inducible factor". British Journal of Haematology. 141 (3): 325–34. doi:10.1111/j.1365-2141.2008.07029.x. PMC 2408651. PMID 18410568.
  22. ^ a b Bruick RK, McKnight SL (November 2001). "A conserved family of prolyl-4-hydroxylases that modify HIF". Science. 294 (5545): 1337–40. Bibcode:2001Sci...294.1337B. doi:10.1126/science.1066373. PMID 11598268. S2CID 9695199.
  23. ^ Karuppagounder SS, Ratan RR (July 2012). "Hypoxia-inducible factor prolyl hydroxylase inhibition: robust new target or another big bust for stroke therapeutics?". Journal of Cerebral Blood Flow and Metabolism. 32 (7): 1347–61. doi:10.1038/jcbfm.2012.28. PMC 3390817. PMID 22415525.
  24. ^ Warnecke C, Griethe W, Weidemann A, Jürgensen JS, Willam C, Bachmann S, Ivashchenko Y, Wagner I, Frei U, Wiesener M, Eckardt KU (June 2003). "Activation of the hypoxia-inducible factor-pathway and stimulation of angiogenesis by application of prolyl hydroxylase inhibitors". FASEB Journal. 17 (9): 1186–8. doi:10.1096/fj.02-1062fje. PMID 12709400. S2CID 45194703.
  25. ^ Selvaraju V, Parinandi NL, Adluri RS, Goldman JW, Hussain N, Sanchez JA, Maulik N (June 2014). "Molecular mechanisms of action and therapeutic uses of pharmacological inhibitors of HIF-prolyl 4-hydroxylases for treatment of ischemic diseases". Antioxidants & Redox Signaling. 20 (16): 2631–65. doi:10.1089/ars.2013.5186. PMC 4026215. PMID 23992027.
  26. ^ Muchnik E, Kaplan J (May 2011). "HIF prolyl hydroxylase inhibitors for anemia". Expert Opinion on Investigational Drugs. 20 (5): 645–56. doi:10.1517/13543784.2011.566861. PMID 21406036. S2CID 21973130.

External links edit

  • Procollagen-proline+dioxygenase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
  • Fe(2+) 2-oxoglutarate dioxygenase domain in PROSITE

January 01, 1970
procollagen, proline, dioxygenase, commonly, known, prolyl, hydroxylase, member, class, enzymes, known, alpha, ketoglutarate, dependent, hydroxylases, these, enzymes, catalyze, incorporation, oxygen, into, organic, substrates, through, mechanism, that, require. Procollagen proline dioxygenase commonly known as prolyl hydroxylase is a member of the class of enzymes known as alpha ketoglutarate dependent hydroxylases These enzymes catalyze the incorporation of oxygen into organic substrates through a mechanism that requires alpha Ketoglutaric acid Fe2 and ascorbate 1 2 This particular enzyme catalyzes the formation of 2S 4R 4 hydroxyproline a compound that represents the most prevalent post translational modification in the human proteome 3 Procollagen proline dioxygenaseAlpha subunits of procollagen proline dioxygenase Image shows substrate binding region orange and the binding groove of tyrosine residues yellow IdentifiersEC no 1 14 11 2CAS no 9028 06 2DatabasesIntEnzIntEnz viewBRENDABRENDA entryExPASyNiceZyme viewKEGGKEGG entryMetaCycmetabolic pathwayPRIAMprofilePDB structuresRCSB PDB PDBe PDBsumGene OntologyAmiGO QuickGOSearchPMCarticlesPubMedarticlesNCBIproteins Contents 1 Enzyme mechanism 2 Enzyme structure 3 Biological function 4 Disease relevance 5 Alternate names 6 References 7 External linksEnzyme mechanism editProcollagen proline dioxygenase catalyzes the following reaction L proline alpha ketoglutaric acid O2 2S 4R 4 hydroxyproline succinate CO2The mechanism for the reaction is similar to that of other dioxygenases and occurs in two distinct stages 3 In the first a highly reactive Fe IV O species is produced Molecular oxygen is bound end on in an axial position producing a dioxygen unit Nucleophilic attack on C2 generates a tetrahedral intermediate with loss of the double bond in the dioxygen unit and bonds to iron and the alpha carbon of 2 oxoglutarate Subsequent elimination of CO2 coincides with the formation of the Fe IV O species The second stage involves the abstraction of the pro R hydrogen atom from C 4 of the proline substrate followed by radical combination which yields hydroxyproline 4 As a consequence of the reaction mechanism one molecule of 2 oxoglutarate is decarboxylated forming succinate This succinate is hydrolyzed and replaced with another 2 oxoglutarate after each reaction and it has been concluded that in the presence of 2 oxoglutarate enzyme bound Fe2 is rapidly converted to Fe3 leading to inactivation of the enzyme 5 Ascorbate is utilized as a cofactor to reduce Fe3 back to Fe2 6 Enzyme structure edit nbsp A closer view of the substrate binding domain of prolyl hydroxylase Tyrosine residues which form the binding groove are displayed in yellow Prolyl hydroxylase is a tetramer with 2 unique subunits 7 The a subunit is 59 kDa and is responsible for both peptide binding and for catalytic activity 8 The peptide binding domain spans residues 140 215 of the a subunit 9 and consists of a concave surface lined with multiple tyrosine residues which interact favorably with the proline rich substrate The active site consists of Fe2 bound to two histidine residues and one aspartate residue a characteristic shared by most 2 oxoglutarate dependent dioxygenases The 55 kDa b subunit is responsible for the enzyme s localization to and retention in the endoplasmic reticulum 10 This subunit is identical to the enzyme known as protein disulfide isomerase 11 Biological function editProlyl hydroxylase catalyzes the formation of hydroxyproline The modification has a significant impact on the stability of collagen the major connective tissue of the human body 12 Specifically hydroxylation increases the melting temperature Tm of helical collagen by 16 C as compared to unhydroxylated collagen 13 a difference that allows the protein to be stable at body temperature Due to the abundance of collagen about one third of total protein in humans and the high occurrence of this modification in collagen hydroxyproline is quantitatively the most abundant post translational modification in humans 14 The enzyme acts specifically on proline contained within the X Pro Gly motif where Pro is proline Because of this motif specific behavior the enzyme also acts on other proteins that contain this same sequence Such proteins include C1q 15 elastins 16 PrP 17 Argonaute 2 18 and conotoxins 19 among others Disease relevance editAs prolyl hydroxylase requires ascorbate as a cofactor to function 5 its absence compromises the enzyme s activity The resulting decreased hydroxylation leads to the disease condition known as scurvy Since stability of collagen is compromised in scurvy patients symptoms include weakening of blood vessels causing purpura petechiae and gingival bleeding Hypoxia inducible factor HIF is an evolutionarily conserved transcription factor 20 that allows the cell to respond physiologically to decreases in oxygen 21 A class of prolyl hydroxylases which act specifically on HIF has been identified 22 hydroxylation of HIF allows the protein to be targeted for degradation 22 HIF prolyl hydroxylase has been targeted by a variety of inhibitors that aim to treat stroke 23 kidney disease 24 ischemia 25 anemia 26 and other important diseases Alternate names editProtocollagen hydroxylase Prolyl hydroxylase Prolyl 4 hydroxylase Protocollagen prolyl hydroxylaseReferences edit Smith TG Talbot NP April 2010 Prolyl hydroxylases and therapeutics Antioxidants amp Redox Signaling 12 4 431 3 doi 10 1089 ars 2009 2901 PMID 19761407 Hutton JJ Trappel AL Udenfriend S July 1966 Requirements for alpha ketoglutarate ferrous ion and ascorbate by collagen proline hydroxylase Biochemical and Biophysical Research Communications 24 2 179 84 doi 10 1016 0006 291x 66 90716 9 PMID 5965224 a b Gorres KL Raines RT April 2010 Prolyl 4 hydroxylase Critical Reviews in Biochemistry and Molecular Biology 45 2 106 24 doi 10 3109 10409231003627991 PMC 2841224 PMID 20199358 Fujita Y Gottlieb A Peterkofsky B Udenfriend S Witkop B 1964 The Preparation of cis and trans 4 H3 L Prolines and Their Use in Studying the Mechanism of Enzymatic Hydroxylation in Chick Embryos Journal of the American Chemical Society 86 21 4709 4716 doi 10 1021 ja01075a036 a b de Jong L Albracht SP Kemp A June 1982 Prolyl 4 hydroxylase activity in relation to the oxidation state of enzyme bound iron The role of ascorbate in peptidyl proline hydroxylation Biochimica et Biophysica Acta 704 2 326 32 doi 10 1016 0167 4838 82 90162 5 PMID 6285984 De Jong L Kemp A May 1984 Stoicheiometry and kinetics of the prolyl 4 hydroxylase partial reaction Biochimica et Biophysica Acta BBA Protein Structure and Molecular Enzymology 787 1 105 11 doi 10 1016 0167 4838 84 90113 4 PMID 6326839 Berg RA Prockop DJ February 1973 Affinity column purification of protocollagen proline hydroxylase from chick embryos and further characterization of the enzyme The Journal of Biological Chemistry 248 4 1175 82 doi 10 1016 S0021 9258 19 44278 6 PMID 4346946 Helaakoski T Vuori K Myllyla R Kivirikko KI Pihlajaniemi T June 1989 Molecular cloning of the alpha subunit of human prolyl 4 hydroxylase the complete cDNA derived amino acid sequence and evidence for alternative splicing of RNA transcripts Proceedings of the National Academy of Sciences of the United States of America 86 12 4392 6 Bibcode 1989PNAS 86 4392H doi 10 1073 pnas 86 12 4392 PMC 287275 PMID 2543975 Pekkala M Hieta R Bergmann U Kivirikko KI Wierenga RK Myllyharju J December 2004 The peptide substrate binding domain of collagen prolyl 4 hydroxylases is a tetratricopeptide repeat domain with functional aromatic residues The Journal of Biological Chemistry 279 50 52255 61 doi 10 1074 jbc M410007200 PMID 15456751 Vuori K Pihlajaniemi T Myllyla R Kivirikko KI November 1992 Site directed mutagenesis of human protein disulphide isomerase effect on the assembly activity and endoplasmic reticulum retention of human prolyl 4 hydroxylase in Spodoptera frugiperda insect cells The EMBO Journal 11 11 4213 7 doi 10 1002 j 1460 2075 1992 tb05515 x PMC 556932 PMID 1327760 Pihlajaniemi T Helaakoski T Tasanen K Myllyla R Huhtala ML Koivu J Kivirikko KI March 1987 Molecular cloning of the beta subunit of human prolyl 4 hydroxylase This subunit and protein disulphide isomerase are products of the same gene The EMBO Journal 6 3 643 9 doi 10 1002 j 1460 2075 1987 tb04803 x PMC 553446 PMID 3034602 Shoulders MD Raines RT 2009 Collagen structure and stability Annual Review of Biochemistry 78 929 58 doi 10 1146 annurev biochem 77 032207 120833 PMC 2846778 PMID 19344236 Berg RA Prockop DJ May 1973 The thermal transition of a non hydroxylated form of collagen Evidence for a role for hydroxyproline in stabilizing the triple helix of collagen Biochemical and Biophysical Research Communications 52 1 115 20 doi 10 1016 0006 291x 73 90961 3 PMID 4712181 Gorres Kelly L Raines Ronald T April 2010 Prolyl 4 hydroxylase Critical Reviews in Biochemistry and Molecular Biology 45 2 106 124 doi 10 3109 10409231003627991 PMC 2841224 PMID 20199358 Muller W Hanauske Abel H Loos M October 1978 Biosynthesis of the first component of complement by human and guinea pig peritoneal macrophages evidence for an independent production of the C1 subunits Journal of Immunology 121 4 1578 84 doi 10 4049 jimmunol 121 4 1578 PMID 701808 S2CID 36397927 Rosenbloom J Cywinski A June 1976 Inhibition of proline hydroxylation does not inhibit secretion of tropoelastin by chick aorta cells FEBS Letters 65 2 246 50 doi 10 1016 0014 5793 76 80490 5 PMID 6335 S2CID 34210226 Gill AC Ritchie MA Hunt LG Steane SE Davies KG Bocking SP Rhie AG Bennett AD Hope J October 2000 Post translational hydroxylation at the N terminus of the prion protein reveals presence of PPII structure in vivo The EMBO Journal 19 20 5324 31 doi 10 1093 emboj 19 20 5324 PMC 314005 PMID 11032800 Qi HH Ongusaha PP Myllyharju J Cheng D Pakkanen O Shi Y Lee SW Peng J Shi Y September 2008 Prolyl 4 hydroxylation regulates Argonaute 2 stability Nature 455 7211 421 4 Bibcode 2008Natur 455 421Q doi 10 1038 nature07186 PMC 2661850 PMID 18690212 Daly NL Craik DJ February 2009 Structural studies of conotoxins IUBMB Life 61 2 144 50 doi 10 1002 iub 158 PMID 19165896 S2CID 8678009 Bacon NC Wappner P O Rourke JF Bartlett SM Shilo B Pugh CW Ratcliffe PJ August 1998 Regulation of the Drosophila bHLH PAS protein Sima by hypoxia functional evidence for homology with mammalian HIF 1 alpha Biochemical and Biophysical Research Communications 249 3 811 6 doi 10 1006 bbrc 1998 9234 PMID 9731218 Smith TG Robbins PA Ratcliffe PJ May 2008 The human side of hypoxia inducible factor British Journal of Haematology 141 3 325 34 doi 10 1111 j 1365 2141 2008 07029 x PMC 2408651 PMID 18410568 a b Bruick RK McKnight SL November 2001 A conserved family of prolyl 4 hydroxylases that modify HIF Science 294 5545 1337 40 Bibcode 2001Sci 294 1337B doi 10 1126 science 1066373 PMID 11598268 S2CID 9695199 Karuppagounder SS Ratan RR July 2012 Hypoxia inducible factor prolyl hydroxylase inhibition robust new target or another big bust for stroke therapeutics Journal of Cerebral Blood Flow and Metabolism 32 7 1347 61 doi 10 1038 jcbfm 2012 28 PMC 3390817 PMID 22415525 Warnecke C Griethe W Weidemann A Jurgensen JS Willam C Bachmann S Ivashchenko Y Wagner I Frei U Wiesener M Eckardt KU June 2003 Activation of the hypoxia inducible factor pathway and stimulation of angiogenesis by application of prolyl hydroxylase inhibitors FASEB Journal 17 9 1186 8 doi 10 1096 fj 02 1062fje PMID 12709400 S2CID 45194703 Selvaraju V Parinandi NL Adluri RS Goldman JW Hussain N Sanchez JA Maulik N June 2014 Molecular mechanisms of action and therapeutic uses of pharmacological inhibitors of HIF prolyl 4 hydroxylases for treatment of ischemic diseases Antioxidants amp Redox Signaling 20 16 2631 65 doi 10 1089 ars 2013 5186 PMC 4026215 PMID 23992027 Muchnik E Kaplan J May 2011 HIF prolyl hydroxylase inhibitors for anemia Expert Opinion on Investigational Drugs 20 5 645 56 doi 10 1517 13543784 2011 566861 PMID 21406036 S2CID 21973130 External links editProcollagen proline dioxygenase at the U S National Library of Medicine Medical Subject Headings MeSH Fe 2 2 oxoglutarate dioxygenase domain in PROSITE Portal nbsp Biology Retrieved from https en wikipedia org w index php title Procollagen proline dioxygenase amp oldid 1215916133, wikipedia, wiki, book, books, library,

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