(+-)-2-Hydroxyglutaric acid

High 2-Hydroxyglutarate levels are associated with gliomas and acute myeloid leukemia. L-2-Hydroxyglutarate can reversibly promote leukemogenesis in vitro. Chronically high levels of L-2-hydroxyglutaric acid are associated with the inborn error of metabolism called: D-2-Hydroxyglutaric Aciduria. The D form is rare, with symptoms including macrocephaly, cardiomyopathy, mental retardation, hypotonia, and cortical blindness.

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. High L-2-Hydroxyglutarate levels are associated with gliomas and acute myeloid leukemia. L-2-Hydroxyglutarate can reversibly promote leukemogenesis in vitro. D-2-hydroxyglutarate mediates its neurotoxicity through activation of N-methyl-D-aspartate receptors. D-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).