Tmic
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Record Information
Version2.0
Creation Date2014-08-29 06:15:36 UTC
Update Date2018-03-21 17:46:15 UTC
Accession NumberT3D4287
Identification
Common NameHomogentisic acid
ClassSmall Molecule
DescriptionHomogentisic acid, also known as melanic acid, is an intermediate in the breakdown or catabolism of tyrosine and phenylalanine. It is generated from the compound p-hydroxyphenylpyruvate through the enzyme p-hydroxyphenylpyruvate dehydrogenase. The resulting homogentisic acid is then broken down into 4-maleylacetoacetate via the enzyme homogentisate 1,2-dioxygenase. Homogentisic acid is also found in other organisms. For instance, it can found in Arbutus unedo (strawberry-tree) honey, in the bacterial plant pathogen Xanthomonas campestris as well as in the yeast Yarrowia lipolytica where it is associated with the production of brown pigments. Homogentisic acid can be oxidatively dimerized to form hipposudoric acid, one of the main constituents of the 'blood sweat' of hippopotamuses. When present in sufficiently high levels, homogentisic acid can function as an osteotoxin and a renal toxin. An osteotoxin is a substance that causes damage to bones and/or joints. A renal toxin causes damage to the kidneys. Chronically high levels of homogentisic acid are associated with alkaptonuria (OMIM: 203500), an inborn error of metabolism. Alkaptonuria is a rare inherited genetic disorder in which the body cannot process the amino acids phenylalanine and tyrosine. It is caused by a mutation in the enzyme homogentisate 1,2-dioxygenase (EC 1.13.11.5), which leads to an accumulation of homogentisic acid in the blood and tissues. Homogentisic acid and its oxidized form benzoquinone acetic acid are excreted in the urine, giving it an unusually dark color. The accumulating homogentisic acid (and benzoquinone acetic acid) causes damage to cartilage (ochronosis, leading to osteoarthritis) and heart valves as well as precipitating as kidney stones and stones in other organs. More specifically, homogentisic acid can be converted to benzoquinone acetic acid (BQA), and the resulting BQA can be readily converted to polymers that resemble the dark skin pigment melanin. These polymers are deposited in the collagen, a connective tissue protein, of particular tissues such as cartilage. This process is called ochronosis (as the tissue looks ochre); ochronotic tissue is stiffened and unusually brittle, impairing its normal function and causing damage.
Compound Type
  • Animal Toxin
  • Food Toxin
  • Metabolite
  • Natural Compound
  • Organic Compound
Chemical Structure
Thumb
Synonyms
Synonym
(2,5-dihydroxyphenyl)-Acetate
(2,5-dihydroxyphenyl)-Acetic acid
2,5-Dihydroxy-a-toluate
2,5-Dihydroxy-a-toluic acid
2,5-Dihydroxy-alpha-toluate
2,5-Dihydroxy-alpha-toluic acid
2,5-Dihydroxy-benzeneacetate
2,5-Dihydroxy-benzeneacetic acid
2,5-Dihydroxyphenylacetate
2,5-Dihydroxyphenylacetic acid
Alcapton
Homogentisate
Homogentisate acid
Homogentisinate
Homogentisinic acid
Melanic acid
Chemical FormulaC8H8O4
Average Molecular Mass168.147 g/mol
Monoisotopic Mass168.042 g/mol
CAS Registry Number451-13-8
IUPAC Name2-(2,5-dihydroxyphenyl)acetic acid
Traditional Namehomogentisic acid
SMILESOC(=O)CC1=CC(O)=CC=C1O
InChI IdentifierInChI=1S/C8H8O4/c9-6-1-2-7(10)5(3-6)4-8(11)12/h1-3,9-10H,4H2,(H,11,12)
InChI KeyInChIKey=IGMNYECMUMZDDF-UHFFFAOYSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as 2(hydroxyphenyl)acetic acids. These are phenylacetic acids that carry a hydroxyl group at the 2-position.
KingdomOrganic compounds
Super ClassBenzenoids
ClassBenzene and substituted derivatives
Sub ClassPhenylacetic acids
Direct Parent2(hydroxyphenyl)acetic acids
Alternative Parents
Substituents
  • 2(hydroxyphenyl)acetic acid
  • Hydroquinone
  • 1-hydroxy-2-unsubstituted benzenoid
  • Phenol
  • Monocarboxylic acid or derivatives
  • Carboxylic acid
  • Carboxylic acid derivative
  • Organic oxygen compound
  • Organic oxide
  • Hydrocarbon derivative
  • Organooxygen compound
  • Carbonyl group
  • Aromatic homomonocyclic compound
Molecular FrameworkAromatic homomonocyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginEndogenous
Cellular Locations
  • Cytoplasm
  • Extracellular
Biofluid LocationsNot Available
Tissue Locations
  • Cartilage
  • Connective Tissue
  • Kidney
Pathways
NameSMPDB LinkKEGG Link
Phenylalanine and Tyrosine MetabolismSMP00008 map00360
Tyrosine MetabolismSMP00006 map00350
AlkaptonuriaSMP00169 Not Available
ApplicationsNot Available
Biological Roles
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point153°C
Boiling PointNot Available
Solubility850 mg/mL at 25°C
LogP0.86
Predicted Properties
PropertyValueSource
Water Solubility8.1 g/LALOGPS
logP0.81ALOGPS
logP1ChemAxon
logS-1.3ALOGPS
pKa (Strongest Acidic)3.57ChemAxon
pKa (Strongest Basic)-5.9ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area77.76 ŲChemAxon
Rotatable Bond Count2ChemAxon
Refractivity41.33 m³·mol⁻¹ChemAxon
Polarizability15.57 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)splash10-000t-0945000000-2f4b9ef9c9ee6e7cd1edView in MoNA
GC-MSGC-MS Spectrum - GC-MS (3 TMS)splash10-0016-3955000000-1cdc64ab3032ff29df29View in MoNA
GC-MSGC-MS Spectrum - EI-B (Non-derivatized)splash10-0a5c-0679000000-97890865f85a79efa2e6View in MoNA
GC-MSGC-MS Spectrum - GC-EI-TOF (Non-derivatized)splash10-000t-0945000000-2f4b9ef9c9ee6e7cd1edView in MoNA
GC-MSGC-MS Spectrum - GC-MS (Non-derivatized)splash10-0016-3955000000-1cdc64ab3032ff29df29View in MoNA
GC-MSGC-MS Spectrum - GC-EI-TOF (Non-derivatized)splash10-0002-0944000000-fd48cc27da661ce24833View in MoNA
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-00di-4900000000-ea40fc8d43156151710cView in MoNA
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (3 TMS) - 70eV, Positivesplash10-014i-5093000000-c342ba08a9bff049fc1cView in MoNA
LC-MS/MSLC-MS/MS Spectrum - Quattro_QQQ 10V, Positive (Annotated)splash10-00di-0900000000-9c395aa569b4b54f8681View in MoNA
LC-MS/MSLC-MS/MS Spectrum - Quattro_QQQ 25V, Positive (Annotated)splash10-00xs-9500000000-ab92286f0d5bc843814bView in MoNA
LC-MS/MSLC-MS/MS Spectrum - Quattro_QQQ 40V, Positive (Annotated)splash10-014l-9000000000-35740a40f4fdf3e84c3cView in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 10V, Negativesplash10-014i-0900000000-f4eba60d63bd99e18b8bView in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 20V, Negativesplash10-00di-0900000000-12e330dc18f0b128b961View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 30V, Negativesplash10-00di-0900000000-4bd53b0472edd31e8609View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 40V, Negativesplash10-00di-0900000000-7121173193a9ba3751a4View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 50V, Negativesplash10-00di-1900000000-04eca21bf25c671b8b6eView in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF (UPLC Q-Tof Premier, Waters) , Negativesplash10-00di-0900000000-780d3740762c2ff89d9aView in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ , negativesplash10-014i-0900000000-f4eba60d63bd99e18b8bView in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ , negativesplash10-00di-0900000000-12e330dc18f0b128b961View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ , negativesplash10-00di-0900000000-4bd53b0472edd31e8609View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ , negativesplash10-00di-0900000000-7121173193a9ba3751a4View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ , negativesplash10-00di-1900000000-04eca21bf25c671b8b6eView in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , negativesplash10-00di-0900000000-9c85164306514c6d4c4bView in MoNA
LC-MS/MSLC-MS/MS Spectrum - , negativesplash10-00di-0900000000-867a4e32ba2d14fd0aadView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0gb9-0900000000-a650bbb95019f3305d03View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-00di-1900000000-94f13b2c7b9726353701View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-05tf-9300000000-968a6390a00dcd77e566View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-01b9-0900000000-0f9d5926d702af7d4d63View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-01b9-1900000000-7f257033d3b1952b3c27View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0a4i-9800000000-bbcb0f0d7348cd1663b1View in MoNA
1D NMR1H NMR SpectrumNot AvailableView in JSpectraViewer
1D NMR1H NMR SpectrumNot AvailableView in JSpectraViewer
1D NMR13C 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 ToxicityExtremely high levels of homogentisic acid are found in patients with the inborn error of metabolism (IEM) called Alkaptonuria. Homogentisic acid spontaneously undergoes oxidation into benzoquinone acetic acid (BQA), which polymerizes forming plasma soluble melanins (PSM). The PSM darkens many tissues (ochronosis - as the tissue looks like ochre), and produces widespread degenerative changes in cartilage and other connective tissues, joints, blood vessels, heart valves and the kidneys. Ochronotic tissue is stiff and unusually brittle. The accumulation of PSM in chondrocytes (the cells that form cartilage) leads to profound alterations in the levels of proteins involved in cell defense, protein folding, and cell organization. An increased post-translational oxidation of proteins, which also involved high molecular weight protein aggregates, has been found to be particularly evident in chondrocytes from patients with alkaptonuria.
MetabolismNot Available
Toxicity ValuesNot Available
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesNot Available
Minimum Risk LevelNot Available
Health EffectsHomogentisic acid is only toxic under chronic exposure. One of the first symptoms of alkaptonuria is darkening of urine on standing (due to the oxidation of homogentisic acid). In most pediatric patients, darkening of urine is the only feature suggesting alkaptonuria. Most patients are usually asymptomatic until age 30. Scleral pigmentation usually starts around age 30. Skin pigmentation becomes obvious by the time patients reach age 40. One of the first sites to be affected is the ear cartilage. There may be discoloration of the forehead, cheeks, axilla, genitalia, palms, nails and soles. Ochronotic arthropathy starts around the 4th decade. Weight-bearing joints like the knees and the intervertebral joints in the spine, as well as the shoulder joints, are involved, with narrowing of joint spaces and disc calcifications. Arthritis is the only disabling effect of this condition and occurs in almost all patients as age advances. Ochronotic arthropathy can be so severe as to require total joint replacement. Pigment deposits can be seen in the larynx, tonsils, esophagus, dura mater, eardrums, trachea, and bronchi. Aortic or mitral valvulitis, calcification of coronary arteries and atherosclerotic plaques are seen after the age of 50 years.
SymptomsNot Available
TreatmentApart from treatment of the complications (such as pain relief using NSAIDs and joint replacement for the cartilage damage), vitamin C has been used to reduce the ochronosis and lowering of the homogentisic acid levels may be attempted with a low-protein diet. Recently the drug nitisinone has been found to suppress homogentisic acid production. Nitrisinone inhibits the enzyme, 4-hydroxyphenylpyruvate dioxygenase, responsible for converting tyrosine to homogentisic acid, thereby blocking the production and accumulation of homogentisic acid. Nitisinone treatment has been shown to cause a 95% reduction in plasma and urinary homogentisic acid.
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB08327
HMDB IDHMDB00130
PubChem Compound ID780
ChEMBL IDNot Available
ChemSpider ID759
KEGG IDC00544
UniProt IDNot Available
OMIM ID
ChEBI ID44747
BioCyc IDNot Available
CTD IDNot Available
Stitch IDNot Available
PDB IDOMD
ACToR IDNot Available
Wikipedia LinkHomogentisic acid
References
Synthesis ReferenceNot Available
MSDSLink
General References
  1. Phornphutkul C, Introne WJ, Perry MB, Bernardini I, Murphey MD, Fitzpatrick DL, Anderson PD, Huizing M, Anikster Y, Gerber LH, Gahl WA: Natural history of alkaptonuria. N Engl J Med. 2002 Dec 26;347(26):2111-21. [12501223 ]
  2. La Du BN Jr: Are we ready to try to cure alkaptonuria? Am J Hum Genet. 1998 Apr;62(4):765-7. [9529368 ]
  3. Concepcion Masip T, Banares Baudet F, Traba ML, Rodriguez de Minon Cifuentes JL: [Alkaptonuria, prostatic calculi, and ectopic ureter]. Actas Urol Esp. 1997 Feb;21(2):167-70. [9214216 ]
  4. Ehongo A, Schrooyen M, Pereleux A: [Important bilateral corneal astigmatism in a case of ocular ochronosis]. Bull Soc Belge Ophtalmol. 2005;(295):17-21. [15849984 ]
  5. Deutsch JC, Santhosh-Kumar CR: Quantitation of homogentisic acid in normal human plasma. J Chromatogr B Biomed Appl. 1996 Feb 23;677(1):147-51. [8925087 ]
  6. Shoemaker JD, Elliott WH: Automated screening of urine samples for carbohydrates, organic and amino acids after treatment with urease. J Chromatogr. 1991 Jan 2;562(1-2):125-38. [2026685 ]
  7. Janocha S, Wolz W, Srsen S, Srsnova K, Montagutelli X, Guenet JL, Grimm T, Kress W, Muller CR: The human gene for alkaptonuria (AKU) maps to chromosome 3q. Genomics. 1994 Jan 1;19(1):5-8. [8188241 ]
  8. de Haas V, Carbasius Weber EC, de Klerk JB, Bakker HD, Smit GP, Huijbers WA, Duran M, Poll-The BT: The success of dietary protein restriction in alkaptonuria patients is age-dependent. J Inherit Metab Dis. 1998 Dec;21(8):791-8. [9870204 ]
  9. Hegedus ZL, Nayak U: Homogentisic acid and structurally related compounds as intermediates in plasma soluble melanin formation and in tissue toxicities. Arch Int Physiol Biochim Biophys. 1994 May-Jun;102(3):175-81. [8000039 ]
  10. Venkataseshan VS, Chandra B, Graziano V, Steinlauf P, Marquet E, Irmiere V, Needle MA: Alkaptonuria and renal failure: a case report and review of the literature. Mod Pathol. 1992 Jul;5(4):464-71. [1495952 ]
  11. Bory C, Boulieu R, Chantin C, Mathieu M: Diagnosis of alcaptonuria: rapid analysis of homogentisic acid by HPLC. Clin Chim Acta. 1990 Jul;189(1):7-11. [2383921 ]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available