L-2-hydroxyglutarate dehydrogenase (L2HGDH)

L-2-hydroxyglutarate dehydrogenase is a mitochondrial, FAD-dependent enzyme that catalyzes the oxidation of L-2-hydroxyglutarate to 2-oxoglutarate (also called alpha-ketoglutarate), integrating into central carbon metabolism and energy production. The enzyme is essential for preventing the accumulation of L-2-hydroxyglutarate, a metabolite that is normally present at low levels in cells. Mutations in the L2HGDH gene lead to a rare neurometabolic disorder, L-2-hydroxyglutaric aciduria, characterized by progressive damage to the brain and neurologic dysfunction. Structurally, L2HGDH belongs to the d-amino acid oxidase family and operates as a mitochondrial membrane-associated protein. The protein is highly conserved and displays strict substrate specificity, and its deficiency disrupts mitochondrial metabolism, particularly in neurons[1][2][3][4][5][6]. No direct therapeutics targeting L2HGDH are in clinical use, but its function is a potential area of metabolic disease research, especially in genetic disorders of metabolism.

Other names

2-hydroxyglutarate dehydrogenasealpha-hydroxyglutarate oxidoreductasealpha-ketoglutarate reductaseC14orf160duranin

N/A (no clinically used drugs targeting this enzyme directly; conceptually, inhibition would cause L-2-hydroxyglutarate accumulation, while activation or replacement could reduce it)