Record Information
Version3.6
Creation Date2005-11-16 15:48:42 UTC
Update Date2013-07-12 16:30:40 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 IUPAC 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
Spectra
Biological Properties
Cellular Locations
  • Mitochondria
  • Endoplasmic reticulum
Biofluid Locations
  • Blood
  • Urine
Tissue Location
  • Fibroblasts
  • Gingiva
  • Kidney
  • Liver
  • Muscle
  • Pancreas
  • Placenta
  • Platelet
  • Prostate
  • Skeletal Muscle
  • Skin
  • Spleen
PathwaysNot Available
Normal Concentrations
BiofluidStatusValueAgeSexConditionReference
BloodDetected and Quantified11.8 (9.9-13.7) uMAdult (>18 years old)BothNormal
  • Geigy Scient...
BloodDetected and Quantified40.0 (28.0-55.0) uMNewborn (0-30 days old)BothNormal
  • Geigy Scient...
BloodDetected and Quantified45.5 (0.00-91.00) uMAdult (>18 years old)BothNormal
BloodDetected and Quantified40.0 +/- 40.0 uMNewborn (0-30 days old)Not SpecifiedCommentNormal
  • Geigy Scient...
BloodDetected and Quantified24.0 +/- 13.0 uMChildren (1-13 year old)MaleCommentNormal
  • Geigy Scient...
BloodDetected and Quantified20.0 +/- 12.0 uMChildren (1-13 year old)FemaleCommentNormal
  • Geigy Scient...
BloodDetected and Quantified20.0 +/- 11.0 uMAdult (>18 years old)MaleCommentNormal
  • Geigy Scient...
BloodDetected and Quantified16.0 +/- 9.0 uMAdult (>18 years old)FemaleCommentNormal
  • Geigy Scient...
BloodDetected and Quantified13.0 (3.0-23.0) uMAdult (>18 years old)BothNormal
UrineDetected and Quantified<3.289 umol/mmol creatinineAdult (>18 years old)BothNormal
    UrineDetected and Quantified1.37 +/- 0.78 umol/mmol creatinineAdult (>18 years old)BothNormal
    UrineDetected and Quantified2.0 (2.15-3.36) umol/mmol creatinineNewborn (0-30 days old)BothNormal
    • Geigy Scient...
    • West Cadwell...
    • Basel, Switz...
    UrineDetected and Quantified15.7 (2.6-29.00) umol/mmol creatinineAdult (>18 years old)BothNormal
    UrineDetected and Quantified2 umol/mmol creatinineAdult (>18 years old)BothNormal
    UrineDetected and Quantified6.5 (2.4-12.5) umol/mmol creatinineAdult (>18 years old)BothCommentNormal
    UrineDetected and Quantified88.17 +/- 49.59 umol/mmol creatinineInfant (0-1 year old)BothNormal
    Abnormal Concentrations
    BiofluidStatusValueAgeSexConditionReference
    BloodDetected and Quantified5.66 +/- 0.67 uMElderly (>65 years old)BothAlzheimer's disease
    BloodDetected and Quantified43.8 +/- 12.5 uMAdult (>18 years old)BothCommentHemodialysis
    BloodDetected and Quantified27.0 +/- 14.1 uMAdult (>18 years old)BothCommentHemodialysis
    BloodDetected and Quantified550.00 (100.00-1000.00) uMChildren (1-13 year old)BothHydroxyprolinemia
    UrineDetected and Quantified190.65 (101.67-279.62) umol/mmol creatinineChildren (1-13 year old)BothHydroxyprolinemia
    UrineDetected and Quantified75 (50-100) umol/mmol creatinineChildren (1-13 year old)BothIminoglycinuria
    Associated Disorders and Diseases
    Disease References
    Alzheimer's disease
    • 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
    • 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
    Iminoglycinuria
    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)Not Available
    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

    Gene Name:
    P4HA2
    Uniprot ID:
    O15460
    Reactions
    L-Proline + Oxoglutaric acid + Oxygen unknown 4-Hydroxyproline + Succinic acid + Carbon dioxidedetails
    Gene Name:
    PYCR1
    Uniprot ID:
    P32322
    Reactions
    4-Hydroxyproline + NAD unknown Pyrroline hydroxycarboxylic acid + NADH + Hydrogen Iondetails
    4-Hydroxyproline + NADP unknown Pyrroline hydroxycarboxylic acid + NADPH + Hydrogen Iondetails
    Gene Name:
    P4HA1
    Uniprot ID:
    P13674
    Reactions
    L-Proline + Oxoglutaric acid + Oxygen unknown 4-Hydroxyproline + Succinic acid + Carbon dioxidedetails
    Gene Name:
    PYCR2
    Uniprot ID:
    Q96C36
    Reactions
    4-Hydroxyproline + NAD unknown Pyrroline hydroxycarboxylic acid + NADH + Hydrogen Iondetails
    4-Hydroxyproline + NADP unknown Pyrroline hydroxycarboxylic acid + NADPH + Hydrogen Iondetails
    Gene Name:
    DPP4
    Uniprot ID:
    P27487
    Gene Name:
    PYCRL
    Uniprot ID:
    Q53H96
    Reactions
    4-Hydroxyproline + NAD unknown Pyrroline hydroxycarboxylic acid + NADH + Hydrogen Iondetails
    4-Hydroxyproline + NADP unknown Pyrroline hydroxycarboxylic acid + NADPH + Hydrogen Iondetails
    Gene Name:
    SLC1A4
    Uniprot ID:
    P43007
    Gene Name:
    P4HA3
    Uniprot ID:
    Q7Z4N8
    Reactions
    L-Proline + Oxoglutaric acid + Oxygen unknown 4-Hydroxyproline + Succinic acid + Carbon dioxidedetails
    Gene Name:
    EGLN1
    Uniprot ID:
    Q9GZT9
    Gene Name:
    EGLN2
    Uniprot ID:
    Q96KS0
    Gene Name:
    EGLN3
    Uniprot ID:
    Q9H6Z9
    Gene Name:
    P4HTM
    Uniprot ID:
    Q9NXG6