D-α-Hydroxyglutaric acid is the major cumulative metabolite of the neurometabolic disease D-2-hydroxyglutaric aciduria. D-α-Hydroxyglutaric acid is a weak competitive antagonist of α-ketoglutarate (α-KG) and inhibits a number of α-KG-dependent dioxygenases, with a Ki value 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 signalling[1][2][3][4][5].In the presence of 50 mM D-2-HG and 100 μM α-ketoglutarate (α-KG), KDM7A partially inhibited both H3K9me2 and H3K27me2 peptides. Addition of 300 μM α-KG was able to reverse the inhibitory effect of 50 mM D-2-HG on Cryptosporidium hidradii KDM7A (CeKDM7A), suggesting that D-2-HG is a weakly competitive inhibitor of α-KG on CeKDM7A demethylases[1].D-α-Hydroxyglutaric acid is a weak inhibitor of TET hydroxylase. In the presence of 0.1 mM α-KG, the addition of 10 mM D-α-Hydroxyglutaric acid resulted in partial inhibition of TET2 (33%), whereas the addition of 50 mM D-α-Hydroxyglutaric acid resulted in greater inhibition of TET2 (83%). D-α Hydroxyglutaric acid inhibited TET1 less significantly[1].
D-α-Hydroxyglutaric acid 动物研究
Animal study
D-α-Hydroxyglutaric acid strongly inhibits glucose utilisation, carbon dioxide production and the respiratory chain in rat cerebral cortex and human skeletal muscle as well as in submembranous cartilage granules of bovine heart, suggesting that aerobic metabolism is impaired. D-α-Hydroxyglutaric acid has also been suggested to be an endogenous excitatory organic acid because it inhibits TET1 through stimulation of specific NMDA glutamate receptors and significantly reduced cell viability in chicken embryo telencephalon and neonatal rat hippocampal neuronal cultures[5].
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