L-2-Hydroxyglutaric aciduria, a disorder of metabolite repair

Abstract

The neurometabolic disorder L-2-hydroxyglutaric aciduria is caused by mutations in a gene present on chromosome 14q22.1 and encoding L-2-hydroxyglutarate dehydrogenase. This FAD-linked mitochondrial enzyme catalyses the irreversible conversion of L-2-hydroxyglutarate to alpha-ketoglutarate. The formation of L-2-hydroxyglutarate results from a side-activity of mitochondrial L-malate dehydrogenase, the enzyme that interconverts oxaloacetate and L-malate, but which also catalyses, very slowly, the NADH-dependent conversion of alpha-ketoglutarate to L-2-hydroxyglutarate. L-2-Hydroxyglutarate has no known physiological function in eukaryotes and most prokaryotes. Its accumulation is toxic to the mammalian brain, causing a leukoencephalopathy and increasing the susceptibility to develop tumours. L-2-Hydroxyglutaric aciduria appears to be the first disease of 'metabolite repair'. © Springer Science+Business Media B.V. 2008.