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].
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