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Record Information
Version3.6
Creation Date2005-11-16 15:48:42 UTC
Update Date2014-10-29 21:47:36 UTC
HMDB IDHMDB00725
Secondary Accession NumbersNone
Metabolite Identification
Common Name4-Hydroxyproline
Description4-Hydroxyproline (or hydroxyproline or Hyp) is a major component of the protein collagen. Hydroxyproline is produced by hydroxylation of the amino acid proline and is, therefore, a post-translationally modified amino acid. Hydroxyproline and proline play key roles for collagen stability. In particular, they permit the sharp twisting of the collagen helix. Hydroxyproline is found in few proteins other than collagen. The only other mammalian protein which includes hydroxyproline is elastin. For this reason, hydroxyproline content has been used as an indicator to determine collagen and/or gelatin amount in tissue or biological samples. Increased serum and urine levels of hydroxyproline have been found in Paget's disease (PMID: 436278 ). Hydroxyproline (Hyp) content in biological fluids is used as a parameter of collagen catabolism, especially bone resorption or tissue degradation. Bedridden and elderly individuals show significantly elevated serum levels of hydroxyproline in comparison to normal, active individuals (PMID: 10706420 ). Elevated levels of urinary hydroxyproline are also indicative of muscle damage (PMID: 21988268 ). Increased reactive oxygen species (ROS) are also known to accelerate collagen degradation. Hydroxyproline levels increase in cases of depression and stress (PMID: 21483218 ).
Structure
Thumb
Synonyms
  1. (2S,4R)-4-hydroxy-2-pyrrolidinecarboxylic acid
  2. (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid
  3. (4R)-4-hydroxy-L-proline
  4. 4-Hydroxy-2-pyrrolidinecarboxylic acid
  5. 4-Hydroxy-L-proline
  6. 4-L-Hydroxyproline
  7. delta-Hydroxyproline
  8. Hydroxiproline
  9. Hydroxy-L-proline
  10. Hydroxy-proline
  11. Hydroxyproline
  12. L-4-Hydroxyproline
  13. L-Hydroxyproline
  14. L-Threo-4-hydroxyproline
  15. LS-hydroxyproline
  16. Oxaceprol
  17. trans-4-Hydroxy-L-proline
  18. trans-4-Hydroxyproline
  19. Trans-hydroxyproline
  20. Trans-L-hydroxyproline
Chemical FormulaC5H9NO3
Average Molecular Weight131.1299
Monoisotopic Molecular Weight131.058243159
IUPAC Name(2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid
Traditional Namehydroxyproline
CAS Registry Number51-35-4
SMILES
O[C@H]1CN[C@@H](C1)C(O)=O
InChI Identifier
InChI=1S/C5H9NO3/c7-3-1-4(5(8)9)6-2-3/h3-4,6-7H,1-2H2,(H,8,9)/t3-,4+/m1/s1
InChI KeyPMMYEEVYMWASQN-DMTCNVIQSA-N
Chemical Taxonomy
KingdomOrganic Compounds
Super ClassAmino Acids, Peptides, and Analogues
ClassAmino Acids and Derivatives
Sub ClassAlpha Amino Acids and Derivatives
Other Descriptors
  • Aliphatic Heteromonocyclic Compounds
  • amino acid zwitterion(ChEBI)
Substituents
  • 1,2 Aminoalcohol
  • Carboxylic Acid
  • Pyrrolidine
  • Pyrrolidine Carboxylic Acid
  • Secondary Alcohol
  • Secondary Aliphatic Amine (Dialkylamine)
Direct ParentAlpha Amino Acids and Derivatives
Ontology
StatusDetected and Quantified
Origin
  • Endogenous
Biofunction
  • Component of Arginine and proline metabolism
ApplicationNot Available
Cellular locations
  • Mitochondria
  • Endoplasmic reticulum
Physical Properties
StateSolid
Experimental Properties
PropertyValueReference
Melting Point274 - 275 °CNot Available
Boiling PointNot AvailableNot Available
Water Solubility361 mg/mL at 25 °CNot Available
LogP-3.17HANSCH,C ET AL. (1995)
Predicted Properties
PropertyValueSource
Water Solubility492 g/LALOGPS
logP-3.3ALOGPS
logP-3.7ChemAxon
logS0.57ALOGPS
pKa (Strongest Acidic)1.64ChemAxon
pKa (Strongest Basic)10.62ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area69.56ChemAxon
Rotatable Bond Count1ChemAxon
Refractivity29.38ChemAxon
Polarizability12.29ChemAxon
Spectra
SpectraGC-MSMS/MSLC-MS1D NMR2D NMR
Biological Properties
Cellular Locations
  • Mitochondria
  • Endoplasmic reticulum
Biofluid Locations
  • Blood
  • Saliva
  • Urine
Tissue Location
  • Fibroblasts
  • Gingiva
  • Kidney
  • Liver
  • Muscle
  • Pancreas
  • Placenta
  • Platelet
  • Prostate
  • Skeletal Muscle
  • Skin
  • Spleen
PathwaysNot Available
Normal Concentrations
BiofluidStatusValueAgeSexConditionReferenceDetails
BloodDetected and Quantified11.8 (9.9-13.7) uMAdult (>18 years old)BothNormal
    • Geigy Scientific ...
details
BloodDetected and Quantified40.0 (28.0-55.0) uMNewborn (0-30 days old)BothNormal
    • Geigy Scientific ...
details
BloodDetected and Quantified45.5 (0.00-91.00) uMAdult (>18 years old)BothNormal details
BloodDetected and Quantified40.0 +/- 40.0 uMNewborn (0-30 days old)Not Specified
Normal
    • Geigy Scientific ...
details
BloodDetected and Quantified24.0 +/- 13.0 uMChildren (1-13 years old)Male
Normal
    • Geigy Scientific ...
details
BloodDetected and Quantified20.0 +/- 12.0 uMChildren (1-13 years old)Female
Normal
    • Geigy Scientific ...
details
BloodDetected and Quantified20.0 +/- 11.0 uMAdult (>18 years old)Male
Normal
    • Geigy Scientific ...
details
BloodDetected and Quantified16.0 +/- 9.0 uMAdult (>18 years old)Female
Normal
    • Geigy Scientific ...
details
BloodDetected and Quantified13.0 (3.0-23.0) uMAdult (>18 years old)BothNormal details
SalivaDetected and Quantified0.873 +/- 0.537 uMAdult (>18 years old)Female
Normal
    • Sugimoto et al. (...
details
SalivaDetected but not QuantifiedNot ApplicableAdult (>18 years old)Not SpecifiedNormal details
SalivaDetected and Quantified1.5 +/- 2.6 uMAdult (>18 years old)Male
Normal
details
SalivaDetected and Quantified1.1 +/- 2.0 uMAdult (>18 years old)Male
Normal
details
SalivaDetected and Quantified0.93 +/- 0.91 uMAdult (>18 years old)BothNormal
    • Dame, ZT. et al. ...
details
SalivaDetected and Quantified<0.25 uMAdult (>18 years old)Male
Normal
details
SalivaDetected and Quantified0.432 +/- 0.431 uMAdult (>18 years old)Male
Normal
    • Sugimoto et al. (...
details
SalivaDetected and Quantified<0.25 uMAdult (>18 years old)Male
Normal
details
UrineDetected and Quantified<3.289 umol/mmol creatinineAdult (>18 years old)BothNormal
    details
    UrineDetected and Quantified1.37 +/- 0.78 umol/mmol creatinineAdult (>18 years old)BothNormal details
    UrineDetected and Quantified2.0 (2.15-3.36) umol/mmol creatinineNewborn (0-30 days old)BothNormal
      • Geigy Scientific ...
      • West Cadwell, N.J...
      • Basel, Switzerlan...
    details
    UrineDetected and Quantified15.7 (2.6-29.00) umol/mmol creatinineAdult (>18 years old)BothNormal details
    UrineDetected and Quantified2 umol/mmol creatinineAdult (>18 years old)BothNormal details
    UrineDetected and Quantified6.5 (2.4-12.5) umol/mmol creatinineAdult (>18 years old)Both
    Normal
    details
    UrineDetected and Quantified88.17 +/- 49.59 umol/mmol creatinineInfant (0-1 year old)BothNormal details
    Abnormal Concentrations
    BiofluidStatusValueAgeSexConditionReferenceDetails
    BloodDetected and Quantified5.66 +/- 0.67 uMElderly (>65 years old)BothAlzheimer's disease details
    BloodDetected and Quantified43.8 +/- 12.5 uMAdult (>18 years old)Both
    Hemodialysis
    details
    BloodDetected and Quantified27.0 +/- 14.1 uMAdult (>18 years old)Both
    Hemodialysis
    details
    BloodDetected and Quantified550.00 (100.00-1000.00) uMChildren (1-13 years old)BothHydroxyprolinemia details
    UrineDetected and Quantified190.65 (101.67-279.62) umol/mmol creatinineChildren (1-13 years old)BothHydroxyprolinemia details
    UrineDetected and Quantified75 (50-100) umol/mmol creatinineChildren (1-13 years old)BothIminoglycinuria details
    Associated Disorders and Diseases
    Disease References
    Alzheimer's disease
    1. Fonteh AN, Harrington RJ, Tsai A, Liao P, Harrington MG: Free amino acid and dipeptide changes in the body fluids from Alzheimer's disease subjects. Amino Acids. 2007 Feb;32(2):213-24. Epub 2006 Oct 10. Pubmed: 17031479
    Hemodialysis
    1. Raj DS, Ouwendyk M, Francoeur R, Pierratos A: Plasma amino acid profile on nocturnal hemodialysis. Blood Purif. 2000;18(2):97-102. Pubmed: 10838467
    Hydroxyprolinemia
    1. MetaGene
    Iminoglycinuria
    1. MetaGene
    Associated OMIM IDs
    DrugBank IDNot Available
    DrugBank Metabolite IDNot Available
    Phenol Explorer Compound IDNot Available
    Phenol Explorer Metabolite IDNot Available
    FoodDB IDFDB013511
    KNApSAcK IDNot Available
    Chemspider ID5605
    KEGG Compound IDC01157
    BioCyc IDL-4-HYDROXY-PROLINE
    BiGG ID36935
    Wikipedia LinkHydroxyproline
    NuGOwiki LinkHMDB00725
    Metagene LinkHMDB00725
    METLIN ID257
    PubChem Compound5810
    PDB IDHYP
    ChEBI ID18095
    References
    Synthesis ReferenceAdams, Elijah; Goldstone, Alfred. Hydroxyproline metabolism. II. Enzymic preparation and properties of D1-pyrroline-3-hydroxy-5-carboxylic acid. Journal of Biological Chemistry (1960), 235 3492-8.
    Material Safety Data Sheet (MSDS)Download (PDF)
    General References
    1. Sreekumar A, Poisson LM, Rajendiran TM, Khan AP, Cao Q, Yu J, Laxman B, Mehra R, Lonigro RJ, Li Y, Nyati MK, Ahsan A, Kalyana-Sundaram S, Han B, Cao X, Byun J, Omenn GS, Ghosh D, Pennathur S, Alexander DC, Berger A, Shuster JR, Wei JT, Varambally S, Beecher C, Chinnaiyan AM: Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature. 2009 Feb 12;457(7231):910-4. Pubmed: 19212411
    2. Cynober LA: Plasma amino acid levels with a note on membrane transport: characteristics, regulation, and metabolic significance. Nutrition. 2002 Sep;18(9):761-6. Pubmed: 12297216
    3. Kelleher PC: Urinary excretion of hydroxyproline, hydroxylysine and hydroxylysine glycosides by patients with Paget's disease of bone and carcinoma with metastases in bone. Clin Chim Acta. 1979 Mar 15;92(3):373-9. Pubmed: 436278
    4. Matsuda Y, Matsumoto K, Yamada A, Ichida T, Asakura H, Komoriya Y, Nishiyama E, Nakamura T: Preventive and therapeutic effects in rats of hepatocyte growth factor infusion on liver fibrosis/cirrhosis. Hepatology. 1997 Jul;26(1):81-9. Pubmed: 9214455
    5. Seibel MJ, Woitge HW: Basic principles and clinical applications of biochemical markers of bone metabolism: biochemical and technical aspects. J Clin Densitom. 1999 Fall;2(3):299-321. Pubmed: 10548826
    6. Akalin FA, Sengun D, Eratalay K, Renda N, Caglayan G: Hydroxyproline and total protein levels in gingiva and gingival crevicular fluid in patients with juvenile, rapidly progressive, and adult periodontitis. J Periodontol. 1993 May;64(5):323-9. Pubmed: 8515361
    7. Akalin FA, Sengun D, Renda N, Eratalay K, Caglayan G: Hydroxyproline and total protein levels in gingiva and gingival crevicular fluid in periodontally healthy human subjects. J Nihon Univ Sch Dent. 1992 Sep;34(3):172-7. Pubmed: 1287145
    8. Lee HS, Shun CT, Chiou LL, Chen CH, Huang GT, Sheu JC: Hydroxyproline content of needle biopsies as an objective measure of liver fibrosis: Emphasis on sampling variability. J Gastroenterol Hepatol. 2005 Jul;20(7):1109-14. Pubmed: 15955222
    9. Akalin FA, Bozkurt FY, Sengun D, Renda N, Kalfa Z, Eratalay K, Velidedeoglu E: Hydroxyproline and total protein levels in gingiva from patients treated with phenytoin and cyclosporine-A. J Nihon Univ Sch Dent. 1996 Mar;38(1):21-30. Pubmed: 8648408
    10. Diaz S, Reyes MV, Zepeda A, Gonzalez GB, Lopez JM, Campino C, Croxatto HB: Norplant((R)) implants and progesterone vaginal rings do not affect maternal bone turnover and density during lactation and after weaning. Hum Reprod. 1999 Oct;14(10):2499-505. Pubmed: 10527977
    11. Fiorucci S, Rizzo G, Antonelli E, Renga B, Mencarelli A, Riccardi L, Morelli A, Pruzanski M, Pellicciari R: Cross-talk between farnesoid-X-receptor (FXR) and peroxisome proliferator-activated receptor gamma contributes to the antifibrotic activity of FXR ligands in rodent models of liver cirrhosis. J Pharmacol Exp Ther. 2005 Oct;315(1):58-68. Epub 2005 Jun 24. Pubmed: 15980055
    12. Kondo A, Ishikawa O, Okada K, Miyachi Y, Abe S, Kuboki Y: Measurement of histidinohydroxylysinonorleucine and hydroxyproline in skin collagen by reversed-phase high-performance liquid chromatography after 9-fluorenylmethyl chloroformate labeling. Anal Biochem. 1997 Oct 15;252(2):255-9. Pubmed: 9344411
    13. Gerling B, Becker M, Waldschmidt J, Rehmann M, Schuppan D: Elevated serum aminoterminal procollagen type-III-peptide parallels collagen accumulation in rats with secondary biliary fibrosis. J Hepatol. 1996 Jul;25(1):79-84. Pubmed: 8836905
    14. Bienkowski RS: A criterion to determine whether cis-4-hydroxyproline is produced in animal tissues. Arch Biochem Biophys. 1984 Mar;229(2):455-8. Pubmed: 6703705
    15. Bellon G, Berg R, Chastang F, Malgras A, Borel JP: Separation and evaluation of the cis and trans isomers of hydroxyprolines: effect of hydrolysis on the epimerization. Anal Biochem. 1984 Feb;137(1):151-5. Pubmed: 6731795
    16. Lindblad WJ, Diegelmann RF: Quantitation of hydroxyproline isomers in acid hydrolysates by high-performance liquid chromatography. Anal Biochem. 1984 May 1;138(2):390-5. Pubmed: 6742416
    17. Shibasaki T, Mori H, Ozaki A: Enzymatic production of trans-4-hydroxy-L-proline by regio- and stereospecific hydroxylation of L-proline. Biosci Biotechnol Biochem. 2000 Apr;64(4):746-50. Pubmed: 10830487
    18. Pickersgill IF, Rapoport H: Preparation of functionalized, conformationally constrained DTPA analogues from L- or D-serine and trans-4-hydroxy-L-proline. Hydroxymethyl substituents on the central acetic acid and on the backbone. J Org Chem. 2000 Jun 30;65(13):4048-57. Pubmed: 10866623
    19. Song IK, Kang YK: Conformational preference and cis-trans isomerization of 4(R)-substituted proline residues. J Phys Chem B. 2006 Feb 2;110(4):1915-27. Pubmed: 16471763
    20. Baldwin JE, Pritchard GJ, Williamson DS: The synthesis of 4-arylsulfanyl-substituted kainoid analogues from trans-4-hydroxy-L-proline. Bioorg Med Chem Lett. 2000 Sep 4;10(17):1927-9. Pubmed: 10987419
    21. Miskolzie M, Gera L, Stewart JM, Kotovych G: The importance of the N-terminal beta-turn in bradykinin antagonists. J Biomol Struct Dyn. 2000 Oct;18(2):249-60. Pubmed: 11089646
    22. Kofoed J, Darbre T, Reymond JL: Dual mechanism of zinc-proline catalyzed aldol reactions in water. Chem Commun (Camb). 2006 Apr 14;(14):1482-4. Epub 2006 Mar 2. Pubmed: 16575434
    23. Kuttan R, Radhakrishnan AN: Studies on bound trans-4-hydroxy-L-proline in sandal (Santalum album L.). Biochem J. 1970 Oct;119(4):651-7. Pubmed: 5493503
    24. Koike K, Li Y, Seo M, Sakurada I, Tezuka K, Uchikura K: Free 4-hydroxyproline content in serum of bedridden aged people is elevated due to fracture. Biol Pharm Bull. 2000 Jan;23(1):101-3. Pubmed: 10706420
    25. Nogueira Ade C, Vale RG, Gomes AL, Dantas EH: The effect of muscle actions on the level of connective tissue damage. Res Sports Med. 2011 Oct;19(4):259-70. doi: 10.1080/15438627.2011.608046. Pubmed: 21988268
    26. Lee KW, Kim SJ, Park JB, Lee KJ: Relationship between depression anxiety stress scale (DASS) and urinary hydroxyproline and proline concentrations in hospital workers. J Prev Med Public Health. 2011 Jan;44(1):9-13. doi: 10.3961/jpmph.2011.44.1.9. Pubmed: 21483218

    Enzymes

    General function:
    Involved in oxidoreductase activity
    Specific function:
    Catalyzes the post-translational formation of 4-hydroxyproline in -Xaa-Pro-Gly- sequences in collagens and other proteins.
    Gene Name:
    P4HA2
    Uniprot ID:
    O15460
    Molecular weight:
    60632.19
    Reactions
    L-Proline + Oxoglutaric acid + Oxygen → 4-Hydroxyproline + Succinic acid + Carbon dioxidedetails
    General function:
    Involved in oxidoreductase activity
    Specific function:
    Housekeeping enzyme that catalyzes the last step in proline biosynthesis. Can utilize both NAD and NADP, but has higher affinity for NAD. Involved in the cellular response to oxidative stress.
    Gene Name:
    PYCR1
    Uniprot ID:
    P32322
    Molecular weight:
    33360.27
    Reactions
    4-Hydroxyproline + NAD → Pyrroline hydroxycarboxylic acid + NADH + Hydrogen Iondetails
    4-Hydroxyproline + NADP → Pyrroline hydroxycarboxylic acid + NADPH + Hydrogen Iondetails
    General function:
    Involved in oxidoreductase activity
    Specific function:
    Catalyzes the post-translational formation of 4-hydroxyproline in -Xaa-Pro-Gly- sequences in collagens and other proteins.
    Gene Name:
    P4HA1
    Uniprot ID:
    P13674
    Molecular weight:
    60966.645
    Reactions
    L-Proline + Oxoglutaric acid + Oxygen → 4-Hydroxyproline + Succinic acid + Carbon dioxidedetails
    General function:
    Involved in oxidoreductase activity
    Specific function:
    Housekeeping enzyme that catalyzes the last step in proline biosynthesis. In some cell types, such as erythrocytes, its primary function may be the generation of NADP(+). Can utilize both NAD and NADP. Has higher affinity for NADP, but higher catalytic efficiency with NADH.
    Gene Name:
    PYCR2
    Uniprot ID:
    Q96C36
    Molecular weight:
    25867.975
    Reactions
    4-Hydroxyproline + NAD → Pyrroline hydroxycarboxylic acid + NADH + Hydrogen Iondetails
    4-Hydroxyproline + NADP → Pyrroline hydroxycarboxylic acid + NADPH + Hydrogen Iondetails
    General function:
    Involved in serine-type endopeptidase activity
    Specific function:
    Cell surface glycoprotein receptor involved in the costimulatory signal essential for T-cell receptor (TCR)-mediated T-cell activation. Acts as a positive regulator of T-cell coactivation, by binding at least ADA, CAV1, IGF2R, and PTPRC. Its binding to CAV1 and CARD11 induces T-cell proliferation and NF- kappa-B activation in a T-cell receptor/CD3-dependent manner. Its interaction with ADA also regulates lymphocyte-epithelial cell adhesion. In association with FAP is involved in the pericellular proteolysis of the extracellular matrix (ECM), the migration and invasion of endothelial cells into the ECM. May be involved in the promotion of lymphatic endothelial cells adhesion, migration and tube formation. When overexpressed, enhanced cell proliferation, a process inhibited by GPC3. Acts also as a serine exopeptidase with a dipeptidyl peptidase activity that regulates various physiological processes by cleaving peptides in the circulation, including many chemokines, mitogenic growth factors, neuropeptides and peptide hormones. Removes N-terminal dipeptides sequentially from polypeptides having unsubstituted N-termini provided that the penultimate residue is proline
    Gene Name:
    DPP4
    Uniprot ID:
    P27487
    Molecular weight:
    88277.9
    General function:
    Involved in oxidoreductase activity
    Specific function:
    Not Available
    Gene Name:
    PYCRL
    Uniprot ID:
    Q53H96
    Molecular weight:
    29892.415
    Reactions
    4-Hydroxyproline + NAD → Pyrroline hydroxycarboxylic acid + NADH + Hydrogen Iondetails
    4-Hydroxyproline + NADP → Pyrroline hydroxycarboxylic acid + NADPH + Hydrogen Iondetails
    General function:
    Involved in sodium:dicarboxylate symporter activity
    Specific function:
    Transporter for alanine, serine, cysteine, and threonine. Exhibits sodium dependence
    Gene Name:
    SLC1A4
    Uniprot ID:
    P43007
    Molecular weight:
    55722.5
    General function:
    Involved in oxidoreductase activity
    Specific function:
    Catalyzes the post-translational formation of 4-hydroxyproline in -Xaa-Pro-Gly- sequences in collagens and other proteins.
    Gene Name:
    P4HA3
    Uniprot ID:
    Q7Z4N8
    Molecular weight:
    61125.675
    Reactions
    L-Proline + Oxoglutaric acid + Oxygen → 4-Hydroxyproline + Succinic acid + Carbon dioxidedetails
    General function:
    Involved in oxidoreductase activity
    Specific function:
    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.
    Gene Name:
    EGLN1
    Uniprot ID:
    Q9GZT9
    Molecular weight:
    46020.585
    General function:
    Involved in oxidoreductase activity
    Specific function:
    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 HIF2A. 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. EGLN2 is involved in regulating hypoxia tolerance and apoptosis in cardiac and skeletal muscle. Also regulates susceptibility to normoxic oxidative neuronal death.
    Gene Name:
    EGLN2
    Uniprot ID:
    Q96KS0
    Molecular weight:
    43650.03
    General function:
    Involved in oxidoreductase activity
    Specific function:
    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 HIF2A. Hydroxylation on the NODD site by EGLN3 appears to require prior hydroxylation on the CODD site. 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. EGLN3 is the most important isozyme in limiting physiological activation of HIFs (particularly HIF2A) in hypoxia. Also hydroxylates PKM in hypoxia, limiting glycolysis. Under normoxia, hydroxylates and regulates the stability of ADRB2. Regulator of cardiomyocyte and neuronal apoptosis. In cardiomyocytes, inhibits the anti-apoptotic effect of BCL2 by disrupting the BAX-BCL2 complex. In neurons, has a NGF-induced proapoptotic effect, probably through regulating CASP3 activity. Also essential for hypoxic regulation of neutrophilic inflammation. Plays a crucial role in DNA damage response (DDR) by hydroxylating TELO2, promoting its interaction with ATR which is required for activation of the ATR/CHK1/p53 pathway.
    Gene Name:
    EGLN3
    Uniprot ID:
    Q9H6Z9
    Molecular weight:
    27261.06
    General function:
    Involved in calcium ion binding
    Specific function:
    Catalyzes the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates HIF1A at 'Pro-402' and 'Pro-564'. May function as a cellular oxygen sensor and, under normoxic conditions, may target HIF through the hydroxylation for proteasomal degradation via the von Hippel-Lindau ubiquitination complex.
    Gene Name:
    P4HTM
    Uniprot ID:
    Q9NXG6
    Molecular weight:
    63111.98