D-α-Hydroxyglutaric acid  (Synonyms: (R)-2-Hydroxyglutarate; (R)-2-Hydroxyglutaric acid; (R)-2-Hydroxypentanedioic acid)

D-α-Hydroxyglutaric acid ((R)-2-Hydroxyglutarate) is the principal metabolite accumulating in neurometabolic disease D-2-hydroxyglutaric aciduria. D-α-Hydroxyglutaric acid is a weak competitive antagonist of α-ketoglutarate (α-KG) and inhibits multiple α-KG-dependent dioxygenases with a K_i of 10.87 mM. D-α-Hydroxyglutaric acid increases reactive oxygen species (ROS) production. D-α-Hydroxyglutaric acid binds and inhibits ATP synthase and inhibits mTOR signaling^{[1][2][3][4][5]}.

D-α-Hydroxyglutaric acid ((R)-2-hydroxyglutarate) accumulates in human cancers carrying neomorphic mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes^[1][2].
A partial inhibition of KDM7A toward both H3K9me2 and H3K27me2 peptides is observed in the presence of 50 mM D-2-HG and 100 μM α-ketoglutarate (α-KG). Addition of 300 μM α-KG is capable of reversing the inhibition of Caenorhabditis elegans KDM7A (CeKDM7A) by 50 mM D-2-HG, indicating that D-2-HG is a weak competitive inhibitor against α-KG toward the CeKDM7A demethylase^[1].
D-α-Hydroxyglutaric acid is a weak inhibitor of TET hydroxylases. In the presence of 0.1 mM of α-KG, addition of 10 mM D-α-Hydroxyglutaric acid results in a partial (33%) inhibition of TET2 and addition of 50 mM D-α-Hydroxyglutaric acid results in more inhibition (83%) of TET2. D-α-Hydroxyglutaric acid exhibits a less pronounced inhibitory effect toward TET1^[1].

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

D-α-Hydroxyglutaric acid strongly inhibits glucose utilization, CO₂ production and the respiratory chain in rat cerebral cortex and human skeletal muscle, as well as in submitochondrial particles from bovine heart, suggesting an impairment of the aerobic metabolism^[5].
D-α-Hydroxyglutaric acid has also been proposed as an endogenous excitotoxic organic acid because it significantly decreased cell viability in neuronal cultures from chick embryo telencephalons and from neonatal rat hippocampus through stimulation of specific NMDA glutamate receptors^[5].
D-α-Hydroxyglutaric acid (0.01-1 mM) significantly increases chemiluminescence and thiobarbituric acid-reactive substances (TBA-RS) and decreased total antioxidant reactivity (TAR) values in the cortical supernatants in 30-day-old-rats^[5].

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

148.11

C₅H₈O₅

13095-47-1

O=C(O)[[email protected]](O)CCC(O)=O

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• [1]. Xu W, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell. 2011 Jan 18;19(1):17-30.  [Content Brief]

  [2]. Fu X, et al. 2-Hydroxyglutarate Inhibits ATP Synthase and mTOR Signaling. Cell Metab. 2015 Sep 1;22(3):508-15.  [Content Brief]

  [3]. Martijn Kranendijk, et al. Progress in understanding 2-hydroxyglutaric acidurias. J Inherit Metab Dis. 2012 Jul;35(4):571-87.  [Content Brief]

  [4]. Martin Böttcher, et al. D-2-hydroxyglutarate interferes with HIF-1α stability skewing T-cell metabolism towards oxidative phosphorylation and impairing Th17 polarization. Oncoimmunology. 2018 Mar 26;7(7):e1445454.  [Content Brief]

  [5]. Alexandra Latini , et al. D-2-hydroxyglutaric acid induces oxidative stress in cerebral cortex of young rats. Eur J Neurosci. 2003 May;17(10):2017-22.  [Content Brief]