L-2-Hydroxyglutaric acid

Chronically high levels of L-2-hydroxyglutaric acid are associated with the inborn error of metabolism called: 2-Hydroxyglutaric Aciduria. L-2-hydroxyglutarate is neurotoxic. L-2-hydroxyglutarate mediates its neurotoxicity through activation of N-methyl-D-aspartate receptors. Symptoms of L-2-Hydroxyglutaric Aciduria include hypotonia, tremors, and epilepsy declining into spongiform leukoencephalopathy, muscular choreodystonia, mental retardation, and psychomotor regression.

2-hydroxyglutarate is an oncometabolite. It is a competitive inhibitor of multiple α-ketoglutarate-dependent dioxygenases, including histone demethylases and the TET family of 5-methlycytosine (5mC) hydroxylases. As a result, high levels of 2-hydroxyglutarate lead to genome-wide histone and DNA methylation alterations, which in turn lead to mutations that ultimately cause cancer. L-2-hydroxyglutarate mediates its neurotoxicity through activation of N-methyl-D-aspartate receptors. L-2-hydroxyglutarate is structurally similar to the excitatory amino acid glutamate and stimulates neurodegeneration by mechanisms well-known for glutamate, NMDA or mitochondrial toxins (A15198).