Human Metabolome Database Version 3.5

Showing metabocard for 4-Hydroxyproline (HMDB00725)

Record Information
Version 3.5
Creation Date 2005-11-16 08:48:42 -0700
Update Date 2013-07-12 10:30:40 -0600
HMDB ID HMDB00725
Secondary Accession Numbers None
Metabolite Identification
Common Name 4-Hydroxyproline
Description 4-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 Link_out). 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 Link_out). Elevated levels of urinary hydroxyproline are also indicative of muscle damage (PMID: 21988268 Link_out). Increased reactive oxygen species (ROS) are also known to accelerate collagen degradation. Hydroxyproline levels increase in cases of depression and stress (PMID: 21483218 Link_out).
Structure Thumb
Download: MOL | SDF | PDB | SMILES | InChI
Display: 2D Structure | 3D Structure
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 Formula C5H9NO3
Average Molecular Weight 131.1299
Monoisotopic Molecular Weight 131.058243159
IUPAC Name (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid
Traditional IUPAC Name hydroxyproline
CAS Registry Number 51-35-4
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 Key PMMYEEVYMWASQN-DMTCNVIQSA-N
Chemical Taxonomy
Kingdom Organic Compounds
Super Class Amino Acids, Peptides, and Analogues
Class Amino Acids and Derivatives
Sub Class Alpha 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 Parent Alpha Amino Acids and Derivatives
Ontology
Status Detected and Quantified
Origin
  • Endogenous
Biofunction
  • Component of Arginine and proline metabolism
Application Not Available
Cellular locations
  • Mitochondria
  • Endoplasmic reticulum
Physical Properties
State Solid
Experimental Properties
Property Value Reference
Melting Point 274 - 275 °C Not Available
Boiling Point Not Available Not Available
Water Solubility 361 mg/mL at 25 °C Not Available
LogP -3.17 HANSCH,C ET AL. (1995)
Predicted Properties
Property Value Source
Water Solubility 492 g/L ALOGPS
LogP -3.31 ALOGPS
LogP -3.7 ChemAxon
LogS 0.57 ALOGPS
pKa (strongest acidic) 1.64 ChemAxon
pKa (strongest basic) 10.62 ChemAxon
Hydrogen Acceptor Count 4 ChemAxon
Hydrogen Donor Count 3 ChemAxon
Polar Surface Area 69.56 A2 ChemAxon
Rotatable Bond Count 1 ChemAxon
Refractivity 29.38 ChemAxon
Polarizability 12.29 ChemAxon
Formal Charge 0 ChemAxon
Physiological Charge 0 ChemAxon
Spectra
Gas-MS Spectrum
13C NMR Spectrum
1H NMR Spectrum
MS/MS Spectrum Quattro_QQQ 10
MS/MS Spectrum Quattro_QQQ 25
MS/MS Spectrum Quattro_QQQ 40
MS/MS Spectrum GC-EI-TOF (Pegasus III TOF-MS system, Leco; GC 6890, Agilent Technologies )
MS/MS Spectrum GC-EI-TOF (Pegasus III TOF-MS system, Leco; GC 6890, Agilent Technologies )
MS/MS Spectrum GC-EI-TOF (Pegasus III TOF-MS system, Leco; GC 6890, Agilent Technologies)
MS/MS Spectrum LC-ESI-QTOF (UPLC Q-Tof Premier, Waters)
MS/MS Spectrum LC-ESI-QTOF (UPLC Q-Tof Premier, Waters)
MS/MS Spectrum GC-MS
MS/MS Spectrum GC-MS
[1H,1H] 2D NMR Spectrum
[1H,13C] 2D NMR Spectrum
Biological Properties
Cellular Locations
  • Mitochondria
  • Endoplasmic reticulum
Biofluid Locations
  • Blood
  • Urine
Tissue Location
  • Muscle
  • Skeletal Muscle
  • Fibroblasts
  • Pancreas
  • Placenta
  • Kidney
  • Liver
  • Prostate
  • Skin
  • Platelet
  • Spleen
  • Gingiva
Pathways Not Available
Normal Concentrations
Biofluid Status Value Age Sex Condition Reference
Blood Detected and Quantified
11.8 (9.9-13.7) uM Adult (>18 years old) Both Normal
  • Geigy Scient...
Blood Detected and Quantified
40.0 (28.0-55.0) uM Newborn (0-30 days old) Both Normal
  • Geigy Scient...
Blood Detected and Quantified
45.5 (0.00-91.00) uM Adult (>18 years old) Both Normal
Blood Detected and Quantified
40.0 +/- 40.0 uM Newborn (0-30 days old) Not Specified Comment Normal
  • Geigy Scient...
Blood Detected and Quantified
24.0 +/- 13.0 uM Children (1-13 year old) Male Comment Normal
  • Geigy Scient...
Blood Detected and Quantified
20.0 +/- 12.0 uM Children (1-13 year old) Female Comment Normal
  • Geigy Scient...
Blood Detected and Quantified
20.0 +/- 11.0 uM Adult (>18 years old) Male Comment Normal
  • Geigy Scient...
Blood Detected and Quantified
16.0 +/- 9.0 uM Adult (>18 years old) Female Comment Normal
  • Geigy Scient...
Blood Detected and Quantified
13.0 (3.0-23.0) uM Adult (>18 years old) Both Normal
Urine Detected and Quantified
<3.289 umol/mmol creatinine Adult (>18 years old) Both Normal
Urine Detected and Quantified
1.37 +/- 0.78 umol/mmol creatinine Adult (>18 years old) Both Normal
Urine Detected and Quantified
2.0 (2.15-3.36) umol/mmol creatinine Newborn (0-30 days old) Both Normal
  • Geigy Scient...
  • West Cadwell...
  • Basel, Switz...
Urine Detected and Quantified
15.7 (2.6-29.00) umol/mmol creatinine Adult (>18 years old) Both Normal
Urine Detected and Quantified
2 umol/mmol creatinine Adult (>18 years old) Both Normal
Urine Detected and Quantified
6.5 (2.4-12.5) umol/mmol creatinine Adult (>18 years old) Both Comment Normal
Urine Detected and Quantified
88.17 +/- 49.59 umol/mmol creatinine Infant (0-1 year old) Both Normal
Abnormal Concentrations
Biofluid Status Value Age Sex Condition Reference
Blood Detected and Quantified 5.66 +/- 0.67 uM Elderly (>65 years old) Both Alzheimer's disease
Blood Detected and Quantified 43.8 +/- 12.5 uM Adult (>18 years old) Both Comment Hemodialysis
Blood Detected and Quantified 27.0 +/- 14.1 uM Adult (>18 years old) Both Comment Hemodialysis
Blood Detected and Quantified 550.00 (100.00-1000.00) uM Children (1-13 year old) Both Hydroxyprolinemia
Urine Detected and Quantified 190.65 (101.67-279.62) umol/mmol creatinine Children (1-13 year old) Both Hydroxyprolinemia
Urine Detected and Quantified 75 (50-100) umol/mmol creatinine Children (1-13 year old) Both Iminoglycinuria
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 Link_out
      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 Link_out
          Hydroxyprolinemia
              Iminoglycinuria
                  Associated OMIM IDs
                  DrugBank ID Not Available
                  DrugBank Metabolite ID Not Available
                  Phenol Explorer Compound ID Not Available
                  Phenol Explorer Metabolite ID Not Available
                  FoodDB ID FDB013511
                  KNApSAcK ID Not Available
                  Chemspider ID 5605 Link_out
                  KEGG Compound ID C01157 Link_out
                  BioCyc ID L-4-HYDROXY-PROLINE Link_out
                  BiGG ID 36935 Link_out
                  Wikipedia Link Hydroxyproline Link_out
                  NuGOwiki Link HMDB00725 Link_out
                  Metagene Link HMDB00725 Link_out
                  METLIN ID 257 Link_out
                  PubChem Compound 5810 Link_out
                  PDB ID HYP Link_out
                  ChEBI ID 18095 Link_out
                  References
                  Synthesis Reference Adams, 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. 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 Link_out
                  2. 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 Link_out
                  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 Link_out
                  4. 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 Link_out
                  5. 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 Link_out
                  6. 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 Link_out
                  7. 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 Link_out
                  8. 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 Link_out
                  9. 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 Link_out
                  10. 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 Link_out
                  11. 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 Link_out
                  12. 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 Link_out
                  13. 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 Link_out
                  14. 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 Link_out
                  15. 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 Link_out
                  16. 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 Link_out
                  17. 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 Link_out
                  18. 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 Link_out
                  19. 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 Link_out
                  20. 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 Link_out
                  21. 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 Link_out
                  22. 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 Link_out
                  23. 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 Link_out
                  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 Link_out
                  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 Link_out
                  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 Link_out

                  Enzymes
                  Name: Prolyl 4-hydroxylase subunit alpha-2
                  Reactions:
                  L-Proline + Oxoglutaric acid + Oxygen unknown 4-Hydroxyproline + Succinic acid + Carbon dioxide details
                  Gene Name: P4HA2
                  Uniprot ID: O15460 Link_out
                  Protein Sequence: FASTA
                  Gene Sequence: FASTA
                  Name: Pyrroline-5-carboxylate reductase 1, mitochondrial
                  Reactions:
                  4-Hydroxyproline + NAD unknown Pyrroline hydroxycarboxylic acid + NADH + Hydrogen Ion details
                  4-Hydroxyproline + NADP unknown Pyrroline hydroxycarboxylic acid + NADPH + Hydrogen Ion details
                  Gene Name: PYCR1
                  Uniprot ID: P32322 Link_out
                  Protein Sequence: FASTA
                  Gene Sequence: FASTA
                  Name: Prolyl 4-hydroxylase subunit alpha-1
                  Reactions:
                  L-Proline + Oxoglutaric acid + Oxygen unknown 4-Hydroxyproline + Succinic acid + Carbon dioxide details
                  Gene Name: P4HA1
                  Uniprot ID: P13674 Link_out
                  Protein Sequence: FASTA
                  Gene Sequence: FASTA
                  Name: Pyrroline-5-carboxylate reductase 2
                  Reactions:
                  4-Hydroxyproline + NAD unknown Pyrroline hydroxycarboxylic acid + NADH + Hydrogen Ion details
                  4-Hydroxyproline + NADP unknown Pyrroline hydroxycarboxylic acid + NADPH + Hydrogen Ion details
                  Gene Name: PYCR2
                  Uniprot ID: Q96C36 Link_out
                  Protein Sequence: FASTA
                  Gene Sequence: FASTA
                  Name: Dipeptidyl peptidase 4
                  Reactions: Not Available
                  Gene Name: DPP4
                  Uniprot ID: P27487 Link_out
                  Protein Sequence: FASTA
                  Gene Sequence: FASTA
                  Name: Pyrroline-5-carboxylate reductase 3
                  Reactions:
                  4-Hydroxyproline + NAD unknown Pyrroline hydroxycarboxylic acid + NADH + Hydrogen Ion details
                  4-Hydroxyproline + NADP unknown Pyrroline hydroxycarboxylic acid + NADPH + Hydrogen Ion details
                  Gene Name: PYCRL
                  Uniprot ID: Q53H96 Link_out
                  Protein Sequence: FASTA
                  Gene Sequence: FASTA
                  Name: Neutral amino acid transporter A
                  Reactions: Not Available
                  Gene Name: SLC1A4
                  Uniprot ID: P43007 Link_out
                  Protein Sequence: FASTA
                  Gene Sequence: FASTA
                  Name: Prolyl 4-hydroxylase subunit alpha-3
                  Reactions:
                  L-Proline + Oxoglutaric acid + Oxygen unknown 4-Hydroxyproline + Succinic acid + Carbon dioxide details
                  Gene Name: P4HA3
                  Uniprot ID: Q7Z4N8 Link_out
                  Protein Sequence: FASTA
                  Gene Sequence: FASTA
                  Name: Egl nine homolog 1
                  Reactions: Not Available
                  Gene Name: EGLN1
                  Uniprot ID: Q9GZT9 Link_out
                  Protein Sequence: FASTA
                  Gene Sequence: FASTA
                  Name: Egl nine homolog 2
                  Reactions: Not Available
                  Gene Name: EGLN2
                  Uniprot ID: Q96KS0 Link_out
                  Protein Sequence: FASTA
                  Gene Sequence: FASTA
                  Name: Egl nine homolog 3
                  Reactions: Not Available
                  Gene Name: EGLN3
                  Uniprot ID: Q9H6Z9 Link_out
                  Protein Sequence: FASTA
                  Gene Sequence: FASTA
                  Name: Transmembrane prolyl 4-hydroxylase
                  Reactions: Not Available
                  Gene Name: P4HTM
                  Uniprot ID: Q9NXG6 Link_out
                  Protein Sequence: FASTA
                  Gene Sequence: FASTA