D-alpha-Hydroxyglutaric Acid Disodium is a multiple-target inhibitor of KDM4A and α-Ketoglutarate(α-KG)-dependent dioxygenase, as well as anNF-κB activator.
D-alpha-Hydroxyglutaric acid disodium is the principal metabolite accumulating in neurometabolic disease D-2-hydroxyglutaric aciduria. D-alpha-Hydroxyglutaric acid ((R)-2-hydroxyglutarate) accumulates in human cancers carrying neomorphic mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes. Tumor-derived IDH1 and IDH2 mutations reduce alpha-KG and accumulate an α-KG antagonist, 2-HG, leading to genome-wide histone and DNA methylation alterations. D-α-Hydroxyglutaric acid is a weak inhibitor of TET hydroxylases. In the presence of 0.1 mM of alpha-KG, addition of 10 mM D-alpha-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-alpha-Hydroxyglutaric acid exhibits a less pronounced inhibitory effect toward TET1[3]. 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. 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[4].
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