Tmic
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Record Information
Version2.0
Creation Date2014-08-29 06:51:06 UTC
Update Date2014-12-24 20:26:48 UTC
Accession NumberT3D4413
Identification
Common Name4-Hydroxyproline
ClassSmall Molecule
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 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 Elevated levels of urinary hydroxyproline are also indicative of muscle damage Increased reactive oxygen species (ROS) are also known to accelerate collagen degradation. Hydroxyproline levels increase in cases of depression and stress (1, 2, 3, 4).
Compound Type
  • Amine
  • Animal Toxin
  • Drug
  • Food Toxin
  • Metabolite
  • Natural Compound
  • Organic Compound
Chemical Structure
Thumb
Synonyms
Synonym
(2S,4R)-4-hydroxy-2-pyrrolidinecarboxylic acid
(2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid
(4R)-4-hydroxy-L-proline
4-Hydroxy-2-pyrrolidinecarboxylic acid
4-Hydroxy-L-proline
4-L-Hydroxyproline
delta-Hydroxyproline
Hydroxiproline
Hydroxy-L-proline
Hydroxy-proline
Hydroxyproline
L-4-Hydroxyproline
L-Hydroxyproline
L-Threo-4-hydroxyproline
LS-hydroxyproline
Oxaceprol
trans-4-Hydroxy-L-proline
trans-4-Hydroxyproline
Trans-hydroxyproline
Trans-L-hydroxyproline
Chemical FormulaC5H9NO3
Average Molecular Mass131.130 g/mol
Monoisotopic Mass131.058 g/mol
CAS Registry Number51-35-4
IUPAC Name(2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid
Traditional Namehypro
SMILES[H][C@]1(O)CN[C@@]([H])(C1)C(O)=O
InChI IdentifierInChI=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 KeyInChIKey=PMMYEEVYMWASQN-DMTCNVIQSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as proline and derivatives. Proline and derivatives are compounds containing proline or a derivative thereof resulting from reaction of proline at the amino group or the carboxy group, or from the replacement of any hydrogen of glycine by a heteroatom.
KingdomOrganic compounds
Super ClassOrganic acids and derivatives
ClassCarboxylic acids and derivatives
Sub ClassAmino acids, peptides, and analogues
Direct ParentProline and derivatives
Alternative Parents
Substituents
  • Proline or derivatives
  • Alpha-amino acid
  • L-alpha-amino acid
  • Pyrrolidine carboxylic acid
  • Pyrrolidine carboxylic acid or derivatives
  • Pyrrolidine
  • 1,2-aminoalcohol
  • Amino acid
  • Secondary alcohol
  • Carboxylic acid
  • Secondary aliphatic amine
  • Monocarboxylic acid or derivatives
  • Azacycle
  • Secondary amine
  • Organoheterocyclic compound
  • Organooxygen compound
  • Organonitrogen compound
  • Alcohol
  • Organic nitrogen compound
  • Organopnictogen compound
  • Organic oxide
  • Hydrocarbon derivative
  • Organic oxygen compound
  • Amine
  • Carbonyl group
  • Aliphatic heteromonocyclic compound
Molecular FrameworkAliphatic heteromonocyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginEndogenous
Cellular Locations
  • Endoplasmic reticulum
  • Membrane
  • Mitochondria
Biofluid LocationsNot Available
Tissue Locations
  • Fibroblasts
  • Gingiva
  • Kidney
  • Liver
  • Muscle
  • Pancreas
  • Placenta
  • Platelet
  • Prostate
  • Skeletal Muscle
  • Skin
  • Spleen
Pathways
NameSMPDB LinkKEGG Link
IminoglycinuriaSMP00193 Not Available
Prolinemia Type IISMP00208 Not Available
ApplicationsNot Available
Biological Roles
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point274 - 275°C
Boiling PointNot Available
Solubility361 mg/mL at 25°C
LogP-3.17
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 Area69.56 ŲChemAxon
Rotatable Bond Count1ChemAxon
Refractivity29.38 m³·mol⁻¹ChemAxon
Polarizability12.29 ųChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash Key
GC-MSGC-MS Spectrum - GC-EI-TOF (Pegasus III TOF-MS system, Leco; GC 6890, Agilent Technologies) (Non-derivatized)splash10-000x-0950000000-5b1c397e26b28e872d20View in MoNA
GC-MSGC-MS Spectrum - GC-EI-TOF (Pegasus III TOF-MS system, Leco; GC 6890, Agilent Technologies) (Non-derivatized)splash10-000x-0950000000-c46b5bba0f41001e3c18View in MoNA
GC-MSGC-MS Spectrum - GC-EI-TOF (Pegasus III TOF-MS system, Leco; GC 6890, Agilent Technologies) (3 TMS)splash10-00di-9530000000-00db00b15ab5341d7d64View in MoNA
GC-MSGC-MS Spectrum - GC-MS (2 TMS)splash10-0a4i-1900000000-c0a869abe2f1e9f8c08eView in MoNA
GC-MSGC-MS Spectrum - GC-MS (3 TMS)splash10-001l-1960000000-abcd0377696d2b52d815View in MoNA
GC-MSGC-MS Spectrum - EI-B (Non-derivatized)splash10-001i-0590000000-75e03328fb2d44469057View in MoNA
GC-MSGC-MS Spectrum - GC-EI-TOF (Non-derivatized)splash10-000x-0950000000-c46b5bba0f41001e3c18View in MoNA
GC-MSGC-MS Spectrum - GC-EI-TOF (Non-derivatized)splash10-00di-9530000000-00db00b15ab5341d7d64View in MoNA
GC-MSGC-MS Spectrum - GC-MS (Non-derivatized)splash10-0a4i-1900000000-c0a869abe2f1e9f8c08eView in MoNA
GC-MSGC-MS Spectrum - GC-MS (Non-derivatized)splash10-001l-1960000000-abcd0377696d2b52d815View in MoNA
GC-MSGC-MS Spectrum - GC-EI-TOF (Non-derivatized)splash10-000x-0940000000-97328204c6b60a244616View in MoNA
GC-MSGC-MS Spectrum - GC-EI-TOF (Non-derivatized)splash10-000x-0940000000-468aeb79950a9e6dadc6View in MoNA
GC-MSGC-MS Spectrum - GC-EI-TOF (Non-derivatized)splash10-0a4i-0900000000-40c0bfa9451caacaf422View in MoNA
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-0a6r-9100000000-af92b4a861832ca4ec13View in MoNA
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (2 TMS) - 70eV, Positivesplash10-02mu-9670000000-81c8390bdfa262fa9b2fView in MoNA
LC-MS/MSLC-MS/MS Spectrum - Quattro_QQQ 10V, Positive (Annotated)splash10-0019-9700000000-ea3ed008938a57d1263cView in MoNA
LC-MS/MSLC-MS/MS Spectrum - Quattro_QQQ 25V, Positive (Annotated)splash10-014r-9000000000-0b76109525f362b600a0View in MoNA
LC-MS/MSLC-MS/MS Spectrum - Quattro_QQQ 40V, Positive (Annotated)splash10-014l-9000000000-477e41e40831316e68acView in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF (UPLC Q-Tof Premier, Waters) , Positivesplash10-0019-9300000000-7228a10f32d447b58ee0View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF (UPLC Q-Tof Premier, Waters) , Negativesplash10-001i-0900000000-11800ca52c6e911f8313View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , negativesplash10-001i-0900000000-11800ca52c6e911f8313View in MoNA
LC-MS/MSLC-MS/MS Spectrum - , negativesplash10-001i-1900000000-b6bba00a324b6eab209fView in MoNA
LC-MS/MSLC-MS/MS Spectrum - , negativesplash10-001i-1900000000-ba9df49a4d967cf8851dView in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-IT , positivesplash10-000i-9000000000-6d125b0bb59101e9ce53View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , positivesplash10-0019-9300000000-7228a10f32d447b58ee0View in MoNA
LC-MS/MSLC-MS/MS Spectrum - , positivesplash10-0019-9600000000-5bcced64c9dfeb96876fView in MoNA
LC-MS/MSLC-MS/MS Spectrum - , positivesplash10-0019-9600000000-b575fa8df5e2d8bb3a99View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-03di-3900000000-a10576d40ff1d7fc707aView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-02t9-9400000000-8b66308781907cdf6304View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-014i-9000000000-7f9d42864b2decdbdd1dView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-001i-2900000000-bfc9154f784caa2e61a7View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-02ar-9800000000-750b3fd4f0e1dcb8ef4cView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-00r6-9000000000-efe39f47f6ee937ded3dView in MoNA
MSMass Spectrum (Electron Ionization)splash10-00ku-9000000000-f5bd67093b2f30a6f62bView in MoNA
1D NMR13C NMR SpectrumNot AvailableView in JSpectraViewer
1D NMR1H NMR SpectrumNot AvailableView in JSpectraViewer
1D NMR1H NMR SpectrumNot AvailableView in JSpectraViewer
2D NMR[1H,1H] 2D NMR SpectrumNot AvailableView in JSpectraViewer
2D NMR[1H,13C] 2D NMR SpectrumNot AvailableView in JSpectraViewer
Toxicity Profile
Route of ExposureNot Available
Mechanism of ToxicityNot Available
MetabolismNot Available
Toxicity ValuesNot Available
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesThis is an endogenously produced metabolite found in the human body. It is used in metabolic reactions, catabolic reactions or waste generation.
Minimum Risk LevelNot Available
Health EffectsNot Available
SymptomsNot Available
TreatmentNot Available
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB08847
HMDB IDHMDB00725
PubChem Compound ID5810
ChEMBL IDCHEMBL352418
ChemSpider ID5605
KEGG IDC01157
UniProt IDNot Available
OMIM ID
ChEBI ID18095
BioCyc IDL-4-HYDROXY-PROLINE
CTD IDNot Available
Stitch IDNot Available
PDB IDHYP
ACToR IDNot Available
Wikipedia LinkHydroxyproline
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.

MSDSLink
General References
  1. 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. [436278 ]
  2. 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. [10706420 ]
  3. 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. [21988268 ]
  4. 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. [21483218 ]
  5. 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. [9214455 ]
  6. 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. [10548826 ]
  7. Cynober LA: Plasma amino acid levels with a note on membrane transport: characteristics, regulation, and metabolic significance. Nutrition. 2002 Sep;18(9):761-6. [12297216 ]
  8. 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. [8515361 ]
  9. 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. [1287145 ]
  10. 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. [15955222 ]
  11. 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. [8648408 ]
  12. 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. [10527977 ]
  13. 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. [15980055 ]
  14. 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. [9344411 ]
  15. 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. [8836905 ]
  16. Bienkowski RS: A criterion to determine whether cis-4-hydroxyproline is produced in animal tissues. Arch Biochem Biophys. 1984 Mar;229(2):455-8. [6703705 ]
  17. 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. [6731795 ]
  18. 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. [6742416 ]
  19. 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. [10830487 ]
  20. 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. [10866623 ]
  21. 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. [16471763 ]
  22. 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. [10987419 ]
  23. 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. [11089646 ]
  24. 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. [16575434 ]
  25. 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. [5493503 ]
  26. 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. doi: 10.1038/nature07762. [19212411 ]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

General Function:
L-proline transmembrane transporter activity
Specific Function:
Neutral amino acid/proton symporter. Has a pH-dependent electrogenic transport activity for small amino acids such as glycine, alanine and proline. Besides small apolar L-amino acids, it also recognize their D-enantiomers and selected amino acid derivatives such as gamma-aminobutyric acid (By similarity).
Gene Name:
SLC36A1
Uniprot ID:
Q7Z2H8
Molecular Weight:
53075.045 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory9000 uMNot AvailableBindingDB 50357233
References
  1. Thondorf I, Voigt V, Schafer S, Gebauer S, Zebisch K, Laug L, Brandsch M: Three-dimensional quantitative structure-activity relationship analyses of substrates of the human proton-coupled amino acid transporter 1 (hPAT1). Bioorg Med Chem. 2011 Nov 1;19(21):6409-18. doi: 10.1016/j.bmc.2011.08.058. Epub 2011 Sep 5. [21955456 ]