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Record Information
Version3.6
Creation Date2005-11-16 15:48:42 UTC
Update Date2016-02-17 00:31:37 UTC
HMDB IDHMDB00606
Secondary Accession Numbers
  • HMDB02323
Metabolite Identification
Common NameD-2-Hydroxyglutaric acid
DescriptionD-2-Hydroxyglutaric acid is a biochemical hallmark of the inherited neurometabolic disorder D-2-hydroxyglutaric aciduria. D-2-hydroxyglutaric aciduria (caused by loss of D2HGDH or gain of function of IDH) is rare, with symptoms including cancer, macrocephaly, cardiomyopathy, mental retardation, hypotonia, and cortical blindness. An elevated urine level of D-2-hydroxyglutarate has been reported patient with spondyloenchondrodysplasia (OMIM 271550 ). D-2-hydroxyglutarate can be converted to α-ketoglutaric acid through the action of 2-hydroxyglutarate dehydrogenase (D2HGDH). Additionally, the enzyme D-3-phosphoglycerate dehydrogenase (PHGDH) can catalyze the NADH-dependent reduction of α-ketoglutarate (AKG) to D-2-hydroxyglutarate (D-2HG). Nyhan et al. (1995) described 3 female patients, 2 of them sibs, who were found to have excess accumulation of D-2-hydroxyglutaric acid in the urine. The phenotype was quite variable, even among the sibs, but included mental retardation, macrocephaly with cerebral atrophy, hypotonia, seizures, and involuntary movements. One of the patients developed severe intermittent vomiting and was given a pyloromyotomy. The electroencephalogram demonstrated hypsarrhythmia. There was an increased concentration of protein in cerebrospinal fluid, an unusual finding in inborn errors of metabolism (OMIM 600721 ). D-2-Hydroxyglutaric acid is also considered to be an oncometabolite (or cancer-causing metabolite). It can be produced via gain-of-function mutations in the cytosolic and mitochondrial isoforms of isocitrate dehydrogenase (IDH). IDH is part of TCA cycle and this compound is generated in high abundance when IDH is mutated. D-2-hydroxyglutarate is sufficiently similar in structure to 2-oxogluratate (2OG) that it is able to inhibit a range of 2OG-dependent dioxygenases, including histone lysine demethylases (KDMs) and members of the ten-eleven translocation (TET) family of 5-methylcytosine (5mC) hydroxylases. This inhibitory effect leads to alterations in the hypoxia induced factor (HIF)-mediated hypoxic response and alterations in gene expression through global epigenetic remodeling. The net effect is that D-2-hydroxyglutarate causes a cascading effect that leads genetic perturbations and malignant transformation.
Structure
Thumb
Synonyms
ValueSource
(R)-2-HydroxyglutarateChEBI
(R)-HydroxyglutarateChEBI
(R)-2-Hydroxyglutaric acidGenerator
(2R)-2-HydroxypentanedioateGenerator
(R)-Hydroxyglutaric acidGenerator
(R)-2-Hydroxy-pentanedioateHMDB
(R)-2-Hydroxy-pentanedioic acidHMDB
(R)-a-HydroxyglutarateHMDB
(R)-a-Hydroxyglutaric acidHMDB
(R)-alpha-HydroxyglutarateHMDB
(R)-alpha-Hydroxyglutaric acidHMDB
2-Hydroxy-D-glutarateHMDB
2-Hydroxy-D-glutaric acidHMDB
2-Hydroxy-delta-glutarateHMDB
2-Hydroxy-delta-glutaric acidHMDB
D-2-HydroxyglutarateHMDB
D-a-HydroxyglutarateHMDB
D-a-Hydroxyglutaric acidHMDB
delta-2-HydroxyglutarateHMDB
delta-2-Hydroxyglutaric acidHMDB
delta-alpha-HydroxyglutarateHMDB
delta-alpha-Hydroxyglutaric acidHMDB
Chemical FormulaC5H8O5
Average Molecular Weight148.114
Monoisotopic Molecular Weight148.037173366
IUPAC Name(2R)-2-hydroxypentanedioic acid
Traditional NameD-2-hydroxyglutaric acid
CAS Registry Number2889-31-8
SMILES
O[C@H](CCC(O)=O)C(O)=O
InChI Identifier
InChI=1S/C5H8O5/c6-3(5(9)10)1-2-4(7)8/h3,6H,1-2H2,(H,7,8)(H,9,10)/t3-/m1/s1
InChI KeyInChIKey=HWXBTNAVRSUOJR-GSVOUGTGSA-N
Chemical Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as hydroxy fatty acids. These are fatty acids in which the chain bears a hydroxyl group.
KingdomOrganic compounds
Super ClassLipids and lipid-like molecules
ClassFatty Acyls
Sub ClassFatty acids and conjugates
Direct ParentHydroxy fatty acids
Alternative Parents
Substituents
  • Hydroxy fatty acid
  • Short-chain hydroxy acid
  • Monosaccharide
  • Hydroxy acid
  • Dicarboxylic acid or derivatives
  • Alpha-hydroxy acid
  • Secondary alcohol
  • Carboxylic acid
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Organooxygen compound
  • Carbonyl group
  • Alcohol
  • Aliphatic acyclic compound
Molecular FrameworkAliphatic acyclic compounds
External Descriptors
Ontology
StatusDetected and Quantified
Origin
  • Endogenous
  • Microbial
Biofunction
  • Metabolic end product
  • Wast product
ApplicationNot Available
Cellular locations
  • Cytoplasm (predicted from logP)
  • Mitochondria
Physical Properties
StateSolid
Experimental Properties
PropertyValueReference
Melting Point> 300 °CNot Available
Boiling PointNot AvailableNot Available
Water SolubilityNot AvailableNot Available
LogPNot AvailableNot Available
Predicted Properties
PropertyValueSource
Water Solubility157.0 mg/mLALOGPS
logP-1ALOGPS
logP-0.82ChemAxon
logS0.03ALOGPS
pKa (Strongest Acidic)3.28ChemAxon
pKa (Strongest Basic)-3.8ChemAxon
Physiological Charge-2ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area94.83 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity29.63 m3·mol-1ChemAxon
Polarizability12.97 Å3ChemAxon
Number of Rings0ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
SpectraNot Available
Biological Properties
Cellular Locations
  • Cytoplasm (predicted from logP)
  • Mitochondria
Biofluid Locations
  • Blood
  • Cerebrospinal Fluid (CSF)
  • Feces
  • Saliva
  • Urine
Tissue Location
  • Brain
Pathways
NameSMPDB LinkKEGG Link
The oncogenic action of D-2-hydroxyglutarate in Hydroxygluaricaciduria SMP02359Not Available
Normal Concentrations
BiofluidStatusValueAgeSexConditionReferenceDetails
BloodDetected and Quantified0.7 +/- 0.2 uMAdult (>18 years old)BothNormal details
FecesDetected but not QuantifiedNot ApplicableNot SpecifiedNot Specified
Normal
details
SalivaDetected but not QuantifiedNot ApplicableAdult (>18 years old)Male
Normal
details
SalivaDetected but not QuantifiedNot ApplicableAdult (>18 years old)Male
Normal
details
SalivaDetected but not QuantifiedNot ApplicableAdult (>18 years old)Male
Normal
details
SalivaDetected but not QuantifiedNot ApplicableAdult (>18 years old)Male
Normal
details
SalivaDetected but not QuantifiedNot ApplicableAdult (>18 years old)Male
Normal
details
SalivaDetected but not QuantifiedNot ApplicableAdult (>18 years old)Male
Normal
details
SalivaDetected but not QuantifiedNot ApplicableAdult (>18 years old)Male
Normal
details
SalivaDetected but not QuantifiedNot ApplicableAdult (>18 years old)Male
Normal
details
SalivaDetected but not QuantifiedNot ApplicableAdult (>18 years old)Male
Normal
details
SalivaDetected but not QuantifiedNot ApplicableAdult (>18 years old)Male
Normal
details
UrineDetected and Quantified11.2 (4.6-33.6) umol/mmol creatinineAdolescent (13-18 years old)BothNormal details
UrineDetected and Quantified<26.15 umol/mmol creatinineChildren (1 - 18 years old)Both
Normal
    • BC Children's Hos...
details
UrineDetected and Quantified51.9 (13.7-97.3) umol/mmol creatinineNewborn (0-30 days old)BothNormal details
UrineDetected and Quantified41.5 (14.6-150.3) umol/mmol creatinineInfant (0-1 year old)BothNormal details
UrineDetected and Quantified12.4 (5.1-24.9) umol/mmol creatinineChildren (1-13 years old)BothNormal details
Abnormal Concentrations
BiofluidStatusValueAgeSexConditionReferenceDetails
BloodDetected and Quantified0.6 (0.30-0.90) uMAdult (>18 years old)BothD-2-hydroxyglutaric aciduria details
BloodDetected and Quantified67.5 (62.0-73.0) uMChildren (1-13 years old)Both2-Hydroxyglutaric Aciduria (D) details
BloodDetected and Quantified61.0 +/- 14.0 uMAdult (>18 years old)BothD-2-Hydroxyglutaric aciduria details
Cerebrospinal Fluid (CSF)Detected and Quantified0.2 (0.1-0.30) uMAdult (>18 years old)BothD-2-hydroxyglutaric aciduria details
Cerebrospinal Fluid (CSF)Detected and Quantified25.0 uMChildren (1-13 years old)Both2-Hydroxyglutaric Aciduria (D) details
UrineDetected and Quantified50.00-4300.00 umol/mmol creatinineChildren (1-13 years old)BothD, L-2-hydroxygluraric aciduria details
UrineDetected but not QuantifiedNot ApplicableChildren (1-13 years old)FemaleSpondyloenchondrodysplasia details
UrineDetected and Quantified33.0 (20.0-46.0) umol/mmol creatinineAdult (>18 years old)BothGlutaric aciduria II details
UrineDetected and Quantified2175.0 (50.0-4300.0) umol/mmol creatinineChildren (1-13 years old)BothGlutaric aciduria II details
UrineDetected and Quantified10.0 (3.0-17.0) umol/mmol creatinineAdult (>18 years old)BothD-2-hydroxyglutaric aciduria details
UrineDetected and Quantified1238.5 (730.0-1747.0) umol/mmol creatinineChildren (1-13 years old)Both2-Hydroxyglutaric Aciduria (D) details
Associated Disorders and Diseases
Disease References
D-2-hydroxyglutaric aciduria
  1. Gibson KM, ten Brink HJ, Schor DS, Kok RM, Bootsma AH, Hoffmann GF, Jakobs C: Stable-isotope dilution analysis of D- and L-2-hydroxyglutaric acid: application to the detection and prenatal diagnosis of D- and L-2-hydroxyglutaric acidemias. Pediatr Res. 1993 Sep;34(3):277-80. [8134166 ]
  2. MetaGene [Link]
  3. MetaGene [Link]
Glutaric aciduria II
  1. MetaGene [Link]
D, L-2-hydroxygluraric aciduria
  1. MetaGene [Link]
Spondyloenchondrodysplasia
  1. Talkhani IS, Saklatvala J, Dwyer J: D-2-hydroxyglutaric aciduria in association with spondyloenchondromatosis. Skeletal Radiol. 2000 May;29(5):289-92. [10883451 ]
Associated OMIM IDs
  • 600721 (D-2-hydroxyglutaric aciduria)
  • 231680 (Glutaric aciduria II)
  • 615182 (D, L-2-hydroxygluraric aciduria)
  • 271550 (Spondyloenchondrodysplasia)
DrugBank IDNot Available
DrugBank Metabolite IDNot Available
Phenol Explorer Compound IDNot Available
Phenol Explorer Metabolite IDNot Available
FoodDB IDFDB022139
KNApSAcK IDNot Available
Chemspider ID388508
KEGG Compound IDC01087
BioCyc IDNot Available
BiGG IDNot Available
Wikipedia LinkNot Available
NuGOwiki LinkHMDB00606
Metagene LinkHMDB00606
METLIN ID5581
PubChem Compound439391
PDB ID2HG
ChEBI ID32796
References
Synthesis ReferenceKobayashi, Hidehiko; Yamaguchi, Koretaka; Yamashita, Takeshi. a-Hydroxyglutaric acid from glutamic acid. Jpn. Tokkyo Koho (1968), 3 pp.
Material Safety Data Sheet (MSDS)Download (PDF)
General References
  1. Gibson KM, ten Brink HJ, Schor DS, Kok RM, Bootsma AH, Hoffmann GF, Jakobs C: Stable-isotope dilution analysis of D- and L-2-hydroxyglutaric acid: application to the detection and prenatal diagnosis of D- and L-2-hydroxyglutaric acidemias. Pediatr Res. 1993 Sep;34(3):277-80. [8134166 ]
  2. van der Knaap MS, Jakobs C, Hoffmann GF, Nyhan WL, Renier WO, Smeitink JA, Catsman-Berrevoets CE, Hjalmarson O, Vallance H, Sugita K, Bowe CM, Herrin JT, Craigen WJ, Buist NR, Brookfield DS, Chalmers RA: D-2-Hydroxyglutaric aciduria: biochemical marker or clinical disease entity? Ann Neurol. 1999 Jan;45(1):111-9. [9894884 ]
  3. Rashed MS, AlAmoudi M, Aboul-Enein HY: Chiral liquid chromatography tandem mass spectrometry in the determination of the configuration of 2-hydroxyglutaric acid in urine. Biomed Chromatogr. 2000 Aug;14(5):317-20. [10960831 ]
  4. da Silva CG, Bueno AR, Schuck PF, Leipnitz G, Ribeiro CA, Wannmacher CM, Wyse AT, Wajner M: D-2-hydroxyglutaric acid inhibits creatine kinase activity from cardiac and skeletal muscle of young rats. Eur J Clin Invest. 2003 Oct;33(10):840-7. [14511354 ]
  5. Clarke NF, Andrews I, Carpenter K, Jakobs C, van der Knaap MS, Kirk EP: D-2-hydroxyglutaric aciduria: a case with an intermediate phenotype and prenatal diagnosis of two affected fetuses. Am J Med Genet A. 2003 Aug 1;120(4):523-7. [12884432 ]

Enzymes

General function:
Involved in phosphoglycerate dehydrogenase activity
Specific function:
Not Available
Gene Name:
PHGDH
Uniprot ID:
O43175
Molecular weight:
56650.03
General function:
Involved in catalytic activity
Specific function:
Catalyzes the oxidation of D-2-hydroxyglutarate to alpha-ketoglutarate.
Gene Name:
D2HGDH
Uniprot ID:
Q8N465
Molecular weight:
56415.58
Reactions
D-2-Hydroxyglutaric acid + acceptor → Oxoglutaric acid + reduced acceptordetails
General function:
Involved in oxidoreductase activity
Specific function:
Catalyzes the cofactor-independent reversible oxidation of gamma-hydroxybutyrate (GHB) to succinic semialdehyde (SSA) coupled to reduction of 2-ketoglutarate (2-KG) to D-2-hydroxyglutarate (D-2-HG). D,L-3-hydroxyisobutyrate and L-3-hydroxybutyrate (L-3-OHB) are also substrates for HOT with 10-fold lower activities.
Gene Name:
ADHFE1
Uniprot ID:
Q8IWW8
Molecular weight:
50307.42
Reactions
(S)-3-Hydroxybutyric acid + Oxoglutaric acid → Acetoacetic acid + D-2-Hydroxyglutaric aciddetails
4-Hydroxybutyric acid + Oxoglutaric acid → Succinic acid semialdehyde + D-2-Hydroxyglutaric aciddetails