Page last updated: 2024-12-04

alpha-hydroxyglutarate

Description Research Excerpts Clinical Trials Roles Classes Pathways Study Profile Bioassays Related Drugs Related Conditions Protein Interactions Research Growth Market Indicators

Description

Alpha-hydroxyglutarate (α-HG) is a non-canonical, five-carbon dicarboxylic acid that exists as two enantiomers: (R)-α-HG and (S)-α-HG. It is structurally similar to α-ketoglutarate (α-KG), a key intermediate in the tricarboxylic acid (TCA) cycle, but differs in the presence of a hydroxyl group instead of a keto group at the α-position. Both enantiomers are formed through different metabolic pathways and have distinct roles in cellular processes. (R)-α-HG is produced by the enzyme L-2-hydroxyglutarate dehydrogenase (L-2-HGDH) and is involved in the metabolism of L-2-hydroxyglutarate, an intermediate in the conversion of L-lysine to α-ketoadipate. (S)-α-HG, on the other hand, is generated by the enzymatic activity of the mitochondrial enzyme α-ketoglutarate dehydrogenase (α-KGDH) and is involved in the TCA cycle. (S)-α-HG can also be produced through the reduction of α-KG by the enzyme NADPH-dependent α-ketoglutarate reductase. Both (R)-α-HG and (S)-α-HG have been implicated in various physiological and pathological conditions, including cancer, neurodegeneration, and metabolic disorders. For instance, elevated levels of (R)-α-HG have been linked to mutations in the L-2-HGDH gene, leading to a rare genetic disorder known as L-2-hydroxyglutaric aciduria. This disorder is characterized by neurological dysfunction, including seizures, intellectual disability, and movement disorders. (S)-α-HG has been shown to have both beneficial and detrimental effects, depending on the context. Studies have reported that (S)-α-HG can act as a substrate for various enzymes, including α-KG-dependent dioxygenases, which play crucial roles in epigenetic regulation, oxygen sensing, and cellular differentiation. However, elevated levels of (S)-α-HG have also been associated with oxidative stress, mitochondrial dysfunction, and tumorigenesis. The precise mechanisms underlying the effects of α-HG are still under investigation, but its involvement in various metabolic pathways, its ability to modulate enzyme activity, and its potential as a signaling molecule make it an important target for further research.'

2-hydroxyglutarate : A dicarboxylic acid anion obtained by deprotonation of at least one of the carboxy groups of 2-hydroxyglutaric acid. [Chemical Entities of Biological Interest (ChEBI), Hastings J, Owen G, Dekker A, Ennis M, Kale N, Muthukrishnan V, Turner S, Swainston N, Mendes P, Steinbeck C. (2016). ChEBI in 2016: Improved services and an expanding collection of metabolites. Nucleic Acids Res]

2-hydroxyglutaric acid : A 2-hydroxydicarboxylic acid that is glutaric acid in which one hydrogen alpha- to a carboxylic acid group is substituted by a hydroxy group. [Chemical Entities of Biological Interest (ChEBI), Hastings J, Owen G, Dekker A, Ennis M, Kale N, Muthukrishnan V, Turner S, Swainston N, Mendes P, Steinbeck C. (2016). ChEBI in 2016: Improved services and an expanding collection of metabolites. Nucleic Acids Res]

Cross-References

ID SourceID
PubMed CID43
CHEMBL ID4870693
CHEBI ID17084
SCHEMBL ID7509
MeSH IDM0071870

Synonyms (39)

Synonym
CHEBI:17084
alpha-hydroxyglutaric acid
pentanedioic acid, 2-hydroxy-
glutaric acid, 2-hydroxy- (6ci,7ci,8ci)
pentanedioic acid, 2-hydroxy- (9ci)
dl-2-hydroxyglutaric
2,3-dideoxypentaric acid
(+/-)-2-hydroxyglutaric acid
glutaric acid, 2-hydroxy-
2-hydroxyglutarate
alpha-hydroxyglutarate
2-hydroxypentanedioic acid
2889-31-8
2-hydroxyglutaric acid
C02630
AKOS006373038
A18581
unii-rs4m3uys95
rs4m3uys95 ,
SCHEMBL7509
HWXBTNAVRSUOJR-UHFFFAOYSA-N
FT-0696794
2-oxidanylpentanedioic acid
LMFA01050483
2-hydroxyglutaric acid disodium salt
Q209412
2-hydroxypentanedioicacid
DTXSID40864360
FT-0775117
SB45575
HY-113038B
EN300-297558
CAA88931
CS-0145757
?-hydroxyglutaric acid
2-hydroxyglutaric acid, (+/-)-
dl-2-hydroxyglutaric acid
CHEMBL4870693 ,
bdbm50570892

Research Excerpts

Pharmacokinetics

ExcerptReferenceRelevance
" We explored the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of ivosidenib in these populations."( Clinical pharmacokinetics and pharmacodynamics of ivosidenib, an oral, targeted inhibitor of mutant IDH1, in patients with advanced solid tumors.
Agresta, S; Dai, D; Fan, B; Gliser, C; Goyal, L; Jiang, L; Liu, G; Lowery, MA; Manyak, E; Mellinghoff, IK; Nimkar, T; Pandya, SS; Prahl Judge, M; Tap, WD; Wen, PY; Yang, H, 2020
)
0.56

Compound-Compound Interactions

ExcerptReferenceRelevance
" Here we developed a strategy by chiral derivatization combined with liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) analysis for highly sensitive determination of D-2HG and L-2HG enantiomers."( Sensitive Determination of Onco-metabolites of D- and L-2-hydroxyglutarate Enantiomers by Chiral Derivatization Combined with Liquid Chromatography/Mass Spectrometry Analysis.
Cheng, QY; Ci, W; Feng, YQ; Huang, W; Ma, Q; Xiong, J; Yuan, BF, 2015
)
0.42
" Herein, we describe a method for the separation and determination of lactic acid and 2-hydroxyglutaric acid enantiomers by chiral derivatization (with l-menthol and acetyl chloride) combined with gas chromatography and mass spectrometry."( Separation and determination of the enantiomers of lactic acid and 2-hydroxyglutaric acid by chiral derivatization combined with gas chromatography and mass spectrometry.
Ding, X; Liang, J; Lin, S; Weng, H, 2018
)
0.48

Bioavailability

ExcerptReferenceRelevance
" Inhibition of glutaminase by allosteric GLS inhibitor bis-2-(5-phenylacetamido-1, 2, 4-thiadiazol-2-yl) ethyl sulfide or by novel, potent, orally bioavailable GLS inhibitor CB-839 reduced intracellular glutamate levels and inhibited growth of AML cells."( Inhibiting glutaminase in acute myeloid leukemia: metabolic dependency of selected AML subtypes.
Baran, N; Cai, T; Chan, SM; Davis, RE; DiNardo, C; Flores, ER; Gonzalez, D; Haferlach, T; Jacamo, R; Konoplev, S; Konopleva, M; Li, W; Lodi, A; Ma, H; Majeti, R; Matre, P; Qi, Y; Samudio, I; Schimmer, AD; Su, X; Sweeney, SR; Tiziani, S; Velez, J; Wang, T, 2016
)
0.43

Dosage Studied

ExcerptRelevanceReference
" There were also increases in plasma 2HG in CER-treated rats on Days 8 and 11 and in TMPD-treated rats at 24 hr after dosing and increases in plasma hexanoylcarnitine in CER-treated rats on Day 11 and in TMPD-treated rats at 6 and 24 hr after dosing."( Plasma 2-hydroxyglutarate and hexanoylcarnitine levels are potential biomarkers for skeletal muscle toxicity in male Fischer 344 rats.
Asai, F; Kobayashi, N; Nezu, Y; Obayashi, H; Shirai, M; Yamoto, T, 2017
)
0.46
[information is derived through text-mining from research data collected from National Library of Medicine (NLM), extracted Dec-2023]

Roles (2)

RoleDescription
metaboliteAny intermediate or product resulting from metabolism. The term 'metabolite' subsumes the classes commonly known as primary and secondary metabolites.
mouse metaboliteAny mammalian metabolite produced during a metabolic reaction in a mouse (Mus musculus).
[role information is derived from Chemical Entities of Biological Interest (ChEBI), Hastings J, Owen G, Dekker A, Ennis M, Kale N, Muthukrishnan V, Turner S, Swainston N, Mendes P, Steinbeck C. (2016). ChEBI in 2016: Improved services and an expanding collection of metabolites. Nucleic Acids Res]

Drug Classes (2)

ClassDescription
2-hydroxydicarboxylic acidAny dicarboxylic acid carrying a hydroxy group on the carbon atom at position alpha to the carboxy group.
dicarboxylic fatty acid
[compound class information is derived from Chemical Entities of Biological Interest (ChEBI), Hastings J, Owen G, Dekker A, Ennis M, Kale N, Muthukrishnan V, Turner S, Swainston N, Mendes P, Steinbeck C. (2016). ChEBI in 2016: Improved services and an expanding collection of metabolites. Nucleic Acids Res]

Pathways (5)

PathwayProteinsCompounds
The Oncogenic Action of 2-Hydroxyglutarate2734
The Oncogenic Action of Succinate2933
The Oncogenic Action of Fumarate2934
The Oncogenic Action of L-2-Hydroxyglutarate in Hydroxyglutaric aciduria2835
The Oncogenic Action of D-2-Hydroxyglutarate in Hydroxyglutaric aciduria2936

Protein Targets (1)

Inhibition Measurements

ProteinTaxonomyMeasurementAverageMin (ref.)Avg (ref.)Max (ref.)Bioassay(s)
Methylcytosine dioxygenase TET2Homo sapiens (human)IC50 (µMol)261.50002.27002.27002.2700AID1763202
[prepared from compound, protein, and bioassay information from National Library of Medicine (NLM), extracted Dec-2023]

Activation Measurements

ProteinTaxonomyMeasurementAverageMin (ref.)Avg (ref.)Max (ref.)Bioassay(s)
Methylcytosine dioxygenase TET2Homo sapiens (human)Kd3.42003.42003.42003.4200AID1763206
[prepared from compound, protein, and bioassay information from National Library of Medicine (NLM), extracted Dec-2023]

Biological Processes (8)

Processvia Protein(s)Taxonomy
leukocyte differentiationMethylcytosine dioxygenase TET2Homo sapiens (human)
5-methylcytosine catabolic processMethylcytosine dioxygenase TET2Homo sapiens (human)
protein O-linked glycosylationMethylcytosine dioxygenase TET2Homo sapiens (human)
response to organic cyclic compoundMethylcytosine dioxygenase TET2Homo sapiens (human)
myeloid cell differentiationMethylcytosine dioxygenase TET2Homo sapiens (human)
positive regulation of gene expression via chromosomal CpG island demethylationMethylcytosine dioxygenase TET2Homo sapiens (human)
positive regulation of transcription by RNA polymerase IIMethylcytosine dioxygenase TET2Homo sapiens (human)
DNA demethylationMethylcytosine dioxygenase TET2Homo sapiens (human)
[Information is prepared from geneontology information from the June-17-2024 release]

Molecular Functions (5)

Processvia Protein(s)Taxonomy
DNA bindingMethylcytosine dioxygenase TET2Homo sapiens (human)
protein bindingMethylcytosine dioxygenase TET2Homo sapiens (human)
ferrous iron bindingMethylcytosine dioxygenase TET2Homo sapiens (human)
zinc ion bindingMethylcytosine dioxygenase TET2Homo sapiens (human)
5-methylcytosine dioxygenase activityMethylcytosine dioxygenase TET2Homo sapiens (human)
[Information is prepared from geneontology information from the June-17-2024 release]

Ceullar Components (3)

Processvia Protein(s)Taxonomy
nucleoplasmMethylcytosine dioxygenase TET2Homo sapiens (human)
chromosomeMethylcytosine dioxygenase TET2Homo sapiens (human)
nucleusMethylcytosine dioxygenase TET2Homo sapiens (human)
[Information is prepared from geneontology information from the June-17-2024 release]

Bioassays (2)

Assay IDTitleYearJournalArticle
AID1763202Inhibition of recombinant human GST-tagged TET2 (1099 to 1936 residues) expressed in Escherichia coli BL21 (DE3)pLysS assessed as reduction in 5hmc level incubated for 2 hrs by ELISA2021Bioorganic & medicinal chemistry, 06-01, Volume: 39SAR insights into TET2 catalytic domain inhibition: Synthesis of 2-Hydroxy-4-Methylene-pentanedicarboxylates.
AID1763206Binding affinity to human recombinant TET2 (1099 to 1936) catalytic domain assessed as dissociation constant by micro-scale thermophoresis analysis2021Bioorganic & medicinal chemistry, 06-01, Volume: 39SAR insights into TET2 catalytic domain inhibition: Synthesis of 2-Hydroxy-4-Methylene-pentanedicarboxylates.
[information is prepared from bioassay data collected from National Library of Medicine (NLM), extracted Dec-2023]

Research

Studies (522)

TimeframeStudies, This Drug (%)All Drugs %
pre-199011 (2.11)18.7374
1990's35 (6.70)18.2507
2000's77 (14.75)29.6817
2010's301 (57.66)24.3611
2020's98 (18.77)2.80
[information is prepared from research data collected from National Library of Medicine (NLM), extracted Dec-2023]

Market Indicators

Research Demand Index: 9.06

According to the monthly volume, diversity, and competition of internet searches for this compound, as well the volume and growth of publications, there is estimated to be weak demand-to-supply ratio for research on this compound.

MetricThis Compound (vs All)
Research Demand Index9.06 (24.57)
Research Supply Index6.30 (2.92)
Research Growth Index5.37 (4.65)
Search Engine Demand Index0.00 (26.88)
Search Engine Supply Index0.00 (0.95)

This Compound (9.06)

All Compounds (24.57)

Study Types

Publication TypeThis drug (%)All Drugs (%)
Trials9 (1.68%)5.53%
Reviews56 (10.47%)6.00%
Case Studies70 (13.08%)4.05%
Observational1 (0.19%)0.25%
Other399 (74.58%)84.16%
[information is prepared from research data collected from National Library of Medicine (NLM), extracted Dec-2023]