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Record Information
Version2.0
Creation Date2014-08-29 06:33:48 UTC
Update Date2018-03-21 17:46:19 UTC
Accession NumberT3D4357
Identification
Common Name3-Hydroxyglutaric acid
ClassSmall Molecule
Description3-Hydroxyglutaric acid is a member of the class of compounds known as dicarboxylic acids and derivatives. These are organic compounds containing exactly two carboxylic acid groups. 3-Hydroxyglutaric acid is soluble (in water) and a weakly acidic compound (based on its pKa). When present in sufficiently high levels, 3-hydroxyglutaric acid can act as act as an acidogen and a metabotoxin. An acidogen is an acidic compound that induces acidosis, which has multiple adverse effects on many organ systems. A metabotoxin is an endogenously produced metabolite that causes adverse health effects at chronically high levels. Chronically high levels of 3-hydroxyglutaric acid are associated with glutaric aciduria type I (glutaric acidemia type I, glutaryl-CoA dehydrogenase deficiency, GA1, or GAT1). GA1 is an inherited disorder in which the body is unable to completely break down the amino acids lysine, hydroxylysine and tryptophan. Excessive levels of their intermediate breakdown products (e.g. glutaric acid, glutaryl-CoA, 3-hydroxyglutaric acid, glutaconic acid) can accumulate and cause damage to the brain (and also other organs). Babies with glutaric acidemia type I are often born with unusually large heads (macrocephaly). Macrocephaly is amongst the earliest signs of GA1. GA1 also causes secondary carnitine deficiency because 3-hydroxyglutaric acid, like other organic acids, is detoxified by carnitine. Abnormally high levels of organic acids in the blood (organic acidemia), urine (organic aciduria), the brain, and other tissues lead to general metabolic acidosis. Acidosis typically occurs when arterial pH falls below 7.35. In infants with acidosis, the initial symptoms include poor feeding, vomiting, loss of appetite, weak muscle tone (hypotonia), and lack of energy (lethargy). These can progress to heart, liver, and kidney abnormalities, seizures, coma, and possibly death. These are also the characteristic symptoms of untreated glutaric aciduria or glutaric acidemia. Many affected children with organic acidemias experience intellectual disability or delayed development. In adults, acidosis or acidemia is characterized by headaches, confusion, feeling tired, tremors, sleepiness, and seizures. It is believed that the excretion of 3-hydroxyglutaric acid is increased during ketosis, which occurs during glutaryl-CoA dehydrogenase deficiency.
Compound Type
  • Animal Toxin
  • Food Toxin
  • Metabolite
  • Natural Compound
  • Organic Compound
Chemical Structure
Thumb
Synonyms
Synonym
3-Hydroxy-glutarate
3-Hydroxy-glutaric acid
3-Hydroxyglutarate
Chemical FormulaC5H8O5
Average Molecular Mass148.114 g/mol
Monoisotopic Mass148.037 g/mol
CAS Registry Number638-18-6
IUPAC Name3-hydroxypentanedioic acid
Traditional Name3-hydroxyglutaric acid
SMILESOC(CC(O)=O)CC(O)=O
InChI IdentifierInChI=1S/C5H8O5/c6-3(1-4(7)8)2-5(9)10/h3,6H,1-2H2,(H,7,8)(H,9,10)
InChI KeyInChIKey=ZQHYXNSQOIDNTL-UHFFFAOYSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as beta hydroxy acids and derivatives. Beta hydroxy acids and derivatives are compounds containing a carboxylic acid substituted with a hydroxyl group on the C3 carbon atom.
KingdomOrganic compounds
Super ClassOrganic acids and derivatives
ClassHydroxy acids and derivatives
Sub ClassBeta hydroxy acids and derivatives
Direct ParentBeta hydroxy acids and derivatives
Alternative Parents
Substituents
  • Short-chain hydroxy acid
  • Beta-hydroxy acid
  • Fatty acid
  • Dicarboxylic acid or derivatives
  • Secondary alcohol
  • Carboxylic acid
  • Carboxylic acid derivative
  • Organic oxygen compound
  • Organic oxide
  • Hydrocarbon derivative
  • Organooxygen compound
  • Carbonyl group
  • Alcohol
  • Aliphatic acyclic compound
Molecular FrameworkAliphatic acyclic compounds
External DescriptorsNot Available
Biological Properties
StatusDetected and Not Quantified
OriginEndogenous
Cellular Locations
  • Cytoplasm
  • Extracellular
Biofluid LocationsNot Available
Tissue Locations
  • Neuron
Pathways
NameSMPDB LinkKEGG Link
Glutaric Aciduria Type ISMP00185 Not Available
ApplicationsNot Available
Biological RolesNot Available
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting PointNot Available
Boiling PointNot Available
SolubilityNot Available
LogPNot Available
Predicted Properties
PropertyValueSource
Water Solubility172 g/LALOGPS
logP-1.2ALOGPS
logP-1ChemAxon
logS0.06ALOGPS
pKa (Strongest Acidic)3.52ChemAxon
pKa (Strongest Basic)-2.9ChemAxon
Physiological Charge-2ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area94.83 ŲChemAxon
Rotatable Bond Count4ChemAxon
Refractivity29.5 m³·mol⁻¹ChemAxon
Polarizability12.81 ųChemAxon
Number of Rings0ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyView
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-0536-9200000000-95922095d2aa1db75f8bJSpectraViewer
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (3 TMS) - 70eV, Positivesplash10-00gs-9081000000-c273d86d7f22986f4bcdJSpectraViewer
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, PositiveNot AvailableJSpectraViewer
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, PositiveNot AvailableJSpectraViewer
LC-MS/MSLC-MS/MS Spectrum - 40V, Negativesplash10-0a4l-9000000000-9249b84ab50ffbbbab00JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 20V, Negativesplash10-0a4i-9100000000-a007a5c975eeaa894298JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 10V, Negativesplash10-0fbi-4900000000-111cef5b8a6a577bf701JSpectraViewer | MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-01qa-1900000000-83e00bd7b92b7f2f9832JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-01qi-5900000000-da4f8a92eae4f7ae9a73JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-000i-9000000000-a255aedbfaa3bce837b8JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0002-2900000000-6ea9c60bf78cda297a39JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0pbj-9800000000-db9f014d4e5dce1cc78fJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0a4i-9100000000-89edd1cbe710cf97835dJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0019-9400000000-3231e946df512b24401aJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-0076-9200000000-4ffdd7ac7861294da783JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-006x-9000000000-f46770ad7298e670b4b7JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0f72-5900000000-c4e9005c7c37f89f6fe3JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-052f-9100000000-de505ca4195705703e19JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0a4l-9000000000-cae7897ab9482c2d43bcJSpectraViewer
1D NMR1H NMR SpectrumNot AvailableJSpectraViewer
1D NMR1H NMR SpectrumNot AvailableJSpectraViewer
1D NMR1H NMR SpectrumNot AvailableJSpectraViewer
2D NMR[1H,13C] 2D NMR SpectrumNot AvailableJSpectraViewer
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 EffectsChronically high levels of 3-hydroxyglutaric acid are associated with Glutaric Aciduria Type I.
SymptomsNot Available
TreatmentNot Available
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB04594
HMDB IDHMDB00428
PubChem Compound ID181976
ChEMBL IDCHEMBL556937
ChemSpider ID158277
KEGG IDNot Available
UniProt IDNot Available
OMIM ID
ChEBI IDNot Available
BioCyc IDR-2-HYDROXYGLUTARATE
CTD IDNot Available
Stitch IDNot Available
PDB ID3HG
ACToR IDNot Available
Wikipedia LinkNot Available
References
Synthesis ReferenceNot Available
MSDSLink
General References
  1. Sauer SW, Okun JG, Fricker G, Mahringer A, Muller I, Crnic LR, Muhlhausen C, Hoffmann GF, Horster F, Goodman SI, Harding CO, Koeller DM, Kolker S: Intracerebral accumulation of glutaric and 3-hydroxyglutaric acids secondary to limited flux across the blood-brain barrier constitute a biochemical risk factor for neurodegeneration in glutaryl-CoA dehydrogenase deficiency. J Neurochem. 2006 May;97(3):899-910. Epub 2006 Mar 29. [16573641 ]
  2. Baric I, Wagner L, Feyh P, Liesert M, Buckel W, Hoffmann GF: Sensitivity and specificity of free and total glutaric acid and 3-hydroxyglutaric acid measurements by stable-isotope dilution assays for the diagnosis of glutaric aciduria type I. J Inherit Metab Dis. 1999 Dec;22(8):867-81. [10604139 ]
  3. Kolker S, Hoffmann GF, Schor DS, Feyh P, Wagner L, Jeffrey I, Pourfarzam M, Okun JG, Zschocke J, Baric I, Bain MD, Jakobs C, Chalmers RA: Glutaryl-CoA dehydrogenase deficiency: region-specific analysis of organic acids and acylcarnitines in post mortem brain predicts vulnerability of the putamen. Neuropediatrics. 2003 Jun;34(5):253-60. [14598231 ]
  4. Wajner M, Kolker S, Souza DO, Hoffmann GF, de Mello CF: Modulation of glutamatergic and GABAergic neurotransmission in glutaryl-CoA dehydrogenase deficiency. J Inherit Metab Dis. 2004;27(6):825-8. [15505388 ]
  5. Nyhan WL, Zschocke J, Hoffmann G, Stein DE, Bao L, Goodman S: Glutaryl-CoA dehydrogenase deficiency presenting as 3-hydroxyglutaric aciduria. Mol Genet Metab. 1999 Mar;66(3):199-204. [10066389 ]
  6. Molven A, Matre GE, Duran M, Wanders RJ, Rishaug U, Njolstad PR, Jellum E, Sovik O: Familial hyperinsulinemic hypoglycemia caused by a defect in the SCHAD enzyme of mitochondrial fatty acid oxidation. Diabetes. 2004 Jan;53(1):221-7. [14693719 ]
  7. Haworth JC, Booth FA, Chudley AE, deGroot GW, Dilling LA, Goodman SI, Greenberg CR, Mallory CJ, McClarty BM, Seshia SS, et al.: Phenotypic variability in glutaric aciduria type I: Report of fourteen cases in five Canadian Indian kindreds. J Pediatr. 1991 Jan;118(1):52-8. [1986098 ]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

General Function:
Sodium-independent organic anion transmembrane transporter activity
Specific Function:
Involved in the renal elimination of endogenous and exogenous organic anions. Functions as organic anion exchanger when the uptake of one molecule of organic anion is coupled with an efflux of one molecule of endogenous dicarboxylic acid (glutarate, ketoglutarate, etc). Mediates the sodium-independent uptake of 2,3-dimercapto-1-propanesulfonic acid (DMPS) (By similarity). Mediates the sodium-independent uptake of p-aminohippurate (PAH), ochratoxin (OTA), acyclovir (ACV), 3'-azido-3-'deoxythymidine (AZT), cimetidine (CMD), 2,4-dichloro-phenoxyacetate (2,4-D), hippurate (HA), indoleacetate (IA), indoxyl sulfate (IS) and 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF), cidofovir, adefovir, 9-(2-phosphonylmethoxyethyl) guanine (PMEG), 9-(2-phosphonylmethoxyethyl) diaminopurine (PMEDAP) and edaravone sulfate. PAH uptake is inhibited by p-chloromercuribenzenesulphonate (PCMBS), diethyl pyrocarbonate (DEPC), sulindac, diclofenac, carprofen, glutarate and okadaic acid (By similarity). PAH uptake is inhibited by benzothiazolylcysteine (BTC), S-chlorotrifluoroethylcysteine (CTFC), cysteine S-conjugates S-dichlorovinylcysteine (DCVC), furosemide, steviol, phorbol 12-myristate 13-acetate (PMA), calcium ionophore A23187, benzylpenicillin, furosemide, indomethacin, bumetamide, losartan, probenecid, phenol red, urate, and alpha-ketoglutarate.
Gene Name:
SLC22A6
Uniprot ID:
Q4U2R8
Molecular Weight:
61815.78 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory98 uMNot AvailableBindingDB 50344960
References
  1. Kouznetsova VL, Tsigelny IF, Nagle MA, Nigam SK: Elucidation of common pharmacophores from analysis of targeted metabolites transported by the multispecific drug transporter-Organic anion transporter1 (Oat1). Bioorg Med Chem. 2011 Jun 1;19(11):3320-40. doi: 10.1016/j.bmc.2011.04.045. Epub 2011 Apr 28. [21571536 ]
General Function:
Receptor binding
Specific Function:
Key enzyme in ketogenesis (ketone body formation). Terminal step in leucine catabolism. Ketone bodies (beta-hydroxybutyrate, acetoacetate and acetone) are essential as an alternative source of energy to glucose, as lipid precursors and as regulators of metabolism.
Gene Name:
HMGCL
Uniprot ID:
P35914
Molecular Weight:
34359.84 Da