You are using an unsupported browser. Please upgrade your browser to a newer version to get the best experience on Human Metabolome Database.
Record Information
Version3.6
Creation Date2012-10-30 10:32:48 UTC
Update Date2016-02-17 00:32:07 UTC
HMDB IDHMDB59655
Secondary Accession NumbersNone
Metabolite Identification
Common Name2-Hydroxyglutarate
Description2-Hydroxyglutarate exists in 2 isomers: L-2-hydroxyglutarate acid and D-2-hydroxyglutarate. Both the D and the L stereoisomers of hydroxyglutaric acid (EC 1.1.99.2) are found in body fluids. In humans it is part of butanoate metabolic pathway and can be produced by phosphoglycerate dehydrogenase (PHGDH). More specifically, the enzyme PHGDH catalyzes the NADH-dependent reduction of α-ketoglutarate (AKG) to D-2-hydroxyglutarate (D-2HG). 2-hydroxyglutarate is also the product of gain-of-function mutations in the cytosolic and mitochondrial isoforms of isocitrate dehydrogenase (IDH). Additionally, 2-hydroxyglutarate can be converted to α-ketoglutaric acid through the action of 2-hydroxyglutarate dehydrogenase (HGDH). Humans have to variants of this enzyme: D-2-hydroxyglutarate dehydrogenase (D2HGDH) and L-2-hydroxyglutarate dehydrogenase (L2HGDH). A deficiency in either of these two enzymes can lead to a disease known as 2-hydroxyglutaric aciduria. L-2-hydroxyglutaric aciduria (caused by loss of L2HGDH) is chronic, with early symptoms such as hypotonia, tremors, and epilepsy declining into spongiform leukoencephalopathy, muscular choreodystonia, mental retardation, and psychomotor regression. 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. 2-hydroxyglutarate was the first oncometabolite (or cancer-causing metabolite) to be formally named or identified. In cancer it is either produced by overexpression of phosphoglycerate dehydrogenase (PHGDH) or is produced in excess by gain-of-function mutations in the cytosolic and mitochondrial isoforms of isocitrate dehydrogenase (IDH). IDH is part of TCA cycle and is generated in high abundance when IDH is mutated. 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 2-hydroxyglutarate causes a cascading effect that leads genetic perturbations and malignant transformation.
Structure
Thumb
Synonyms
ValueSource
alpha-Hydroxyglutaric acidChEBI
a-HydroxyglutarateGenerator
a-Hydroxyglutaric acidGenerator
alpha-HydroxyglutarateGenerator
α-hydroxyglutarateGenerator
α-hydroxyglutaric acidGenerator
2-HydroxyglutarateGenerator
Chemical FormulaC5H8O5
Average Molecular Weight148.114
Monoisotopic Molecular Weight148.037173366
IUPAC Name2-hydroxypentanedioic acid
Traditional Name2-hydroxyglutaric acid
CAS Registry NumberNot Available
SMILES
OC(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)
InChI KeyInChIKey=HWXBTNAVRSUOJR-UHFFFAOYSA-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 DescriptorsNot Available
Ontology
StatusDetected and Quantified
Origin
  • Endogenous
  • Microbial
Biofunction
  • Component of Butanoate metabolism
  • Metabolic end product
  • Waste product
ApplicationNot Available
Cellular locations
  • Cytoplasm (predicted from logP)
  • Mitochondria
Physical Properties
StateSolid
Experimental Properties
PropertyValueReference
Melting PointNot AvailableNot 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
Spectra
Spectrum TypeDescriptionSplash Key
Predicted GC-MSPredicted GC-MS Spectrum - GC-MSNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-001i-2900000000-4a286f23e047b386c273View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-0lz0-9600000000-6b6214d1086f381022a0View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0a4r-9100000000-02ce88ad8bf7c4b7f22aView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-002b-2900000000-6750865d94d1d2564b29View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0zi9-8900000000-8cdd78454ba0d2069b3eView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0a4i-9100000000-1ef9312d29d127c85bf8View in MoNA
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 2-hydroxyglutarateSMP02291Not Available
The oncogenic action of D-2-hydroxyglutarate in Hydroxygluaricaciduria SMP02359Not Available
The oncogenic action of FumarateSMP02295Not Available
The oncogenic action of L-2-hydroxyglutarate in HydroxygluaricaciduriaSMP02358Not Available
The oncogenic action of SuccinateSMP02292Not Available
Normal Concentrations
BiofluidStatusValueAgeSexConditionReferenceDetails
BloodDetected and Quantified0.7 +/- 0.2 uMAdult (>18 years old)BothNormal details
BloodDetected and Quantified1.5 (0.0-1.5) uMAdult (>18 years old)BothNormal details
Cerebrospinal Fluid (CSF)Detected and Quantified1 uMChildren (1-13 years old)BothNormal details
Cerebrospinal Fluid (CSF)Detected and Quantified1.0 +/- 1/0 uMAdult (>18 years old)Not SpecifiedNormal details
FecesDetected but not QuantifiedNot ApplicableAdult (>18 years old)Not SpecifiedNormal details
FecesDetected but not QuantifiedNot ApplicableAdult (>18 years old)Both
Normal
details
FecesDetected but not QuantifiedNot ApplicableAdult (>18 years old)Both
Normal
details
SalivaDetected and Quantified0.881 +/- 1.13 uMAdult (>18 years old)Female
Normal
    • Sugimoto et al. (...
details
SalivaDetected and Quantified1.08 +/- 0.629 uMAdult (>18 years old)Female
Normal
    • Sugimoto et al. (...
details
SalivaDetected and Quantified1.44 +/- 1.33 uMAdult (>18 years old)Female
Normal
    • Sugimoto et al. (...
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
SalivaDetected but not QuantifiedNot ApplicableAdult (>18 years old)Both
Normal
    • Zerihun T. Dame, ...
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 (1-13 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
UrineDetected and Quantified11.2 (4.6-33.6) umol/mmol creatinineAdolescent (13-18 years old)BothNormal details
UrineDetected and Quantified24.379 umol/mmol creatinineChildren (1-13 years old)Not Specified
Normal
    • Mordechai, Hien, ...
details
UrineDetected but not QuantifiedNot ApplicableAdult (>18 years old)Both
Normal
details
UrineDetected and Quantified2.2 (0.8-52) umol/mmol creatinineAdult (>18 years old)BothNormal details
UrineDetected and Quantified33.0 (13.3-77.9) umol/mmol creatinineAdult (>18 years old)Both
Normal
details
UrineDetected and Quantified33.0 (20.0-46.0) umol/mmol creatinineAdult (>18 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
BloodDetected and Quantified47.0 +/- 13.0 uMAdult (>18 years old)BothL-2-hydroxyglutaric aciduria details
BloodDetected and Quantified0.75 (0.0-1.5) uMAdult (>18 years old)Both2-hydroxyglutaric aciduria details
BloodDetected and Quantified33.3 (7.0-61.0) uMChildren (1-13 years old)BothL-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 Quantified61.074 +/- 36.982 umol/mmol creatinineChildren (1-13 years old)Both
Eosinophilic esophagitis
    • Mordechai, Hien, ...
details
UrineDetected and Quantified50.00-4300.00 umol/mmol creatinineChildren (1-13 years old)BothD, L-2-hydroxygluraric aciduria 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]
L-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]
Glutaric aciduria II
  1. MetaGene [Link]
Eosinophilic esophagitis
  1. Mordechai, Hien, and David S. Wishart
D, L-2-hydroxygluraric aciduria
  1. MetaGene [Link]
Associated OMIM IDs
  • 600721 (D-2-hydroxyglutaric aciduria)
  • 236792 (L-2-hydroxyglutaric aciduria)
  • 231680 (Glutaric aciduria II)
  • 610247 (Eosinophilic esophagitis)
  • 615182 (D, L-2-hydroxygluraric aciduria)
DrugBank IDNot Available
DrugBank Metabolite IDNot Available
Phenol Explorer Compound IDNot Available
Phenol Explorer Metabolite IDNot Available
FoodDB IDNot Available
KNApSAcK IDNot Available
Chemspider ID42
KEGG Compound IDC02630
BioCyc IDNot Available
BiGG IDNot Available
Wikipedia LinkNot Available
NuGOwiki LinkHMDB59655
Metagene LinkHMDB59655
METLIN IDNot Available
PubChem Compound43
PDB IDNot Available
ChEBI ID17084
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. Guneral F, Bachmann C: Age-related reference values for urinary organic acids in a healthy Turkish pediatric population. Clin Chem. 1994 Jun;40(6):862-6. [8087979 ]
  2. 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 ]
  3. 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 ]
  4. 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 ]
  5. 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 ]
  6. 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 ]
  7. Fujitake J, Ishikawa Y, Fujii H, Nishimura K, Hayakawa K, Inoue F, Terada N, Okochi M, Tatsuoka Y: L-2-hydroxyglutaric aciduria: two Japanese adult cases in one family. J Neurol. 1999 May;246(5):378-82. [10399870 ]
  8. Barth PG, Hoffmann GF, Jaeken J, Lehnert W, Hanefeld F, van Gennip AH, Duran M, Valk J, Schutgens RB, Trefz FK, et al.: L-2-hydroxyglutaric acidemia: a novel inherited neurometabolic disease. Ann Neurol. 1992 Jul;32(1):66-71. [1642474 ]
  9. de Klerk JB, Huijmans JG, Stroink H, Robben SG, Jakobs C, Duran M: L-2-hydroxyglutaric aciduria: clinical heterogeneity versus biochemical homogeneity in a sibship. Neuropediatrics. 1997 Dec;28(6):314-7. [9453028 ]

Enzymes

General function:
Involved in phosphoglycerate dehydrogenase activity
Specific function:
Not Available
Gene Name:
PHGDH
Uniprot ID:
O43175
Molecular weight:
56650.03
Reactions
2-Hydroxyglutarate + NAD → Oxoglutaric acid + NADHdetails
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
General function:
Involved in 2-hydroxyglutarate dehydrogenase activity
Specific function:
Not Available
Gene Name:
L2HGDH
Uniprot ID:
Q9H9P8
Molecular weight:
50315.58
Reactions
2-Hydroxyglutarate + FAD → Oxoglutaric acid + FADHdetails
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