Hydroxyglutaric aciduria is a rare genetic disorder. Both isoforms are believed to have autosomal recessive inheritance. The compound 2-hydroxyglutarate is the product of gain-of-function mutations producing mutIDH1 and mutIDH2 in the cytosolic and mitochondrial isoforms of isocitrate dehydrogenase (IDH). This compound is derived from the TCA cycle. The compound 2-hydroxyglutarate shares enough structural similarity to 2-oxogluratate (2OG) to inhibit a range of 2OG-dependent dioxygenases, including histone lysine demethylases (KDMs) and the ten-eleven translocation (TET) family of 5-methylcytosine (5mC) hydroxylases. This results in modulations of HIF-mediated hypoxia responses and alterations in gene expression through global epigenetic remodelling that may contribute to malignant transformation. L-2-hydroxyglutarate dehydrogenase (L2HGDH) converts L-2-hydroxyglutarate to α-ketoglutaric acid. L-2-Hydroxyglutarate is an oncometabolite and is produced by gain-of-function IDH mutations. When IDH is mutated, L-2-Hydroxyglutaric acid production is increased. L-2-hydroxyglutarate is a competitive inhibitor of 2OG-dependent dioxygenases resulting in genetic changes and malignancies.

The Oncogenic Action of L-2-Hydroxyglutarate in Hydroxyglutaric aciduria References