l-2-Hydroxyglutaric aciduria, a disorder of metabolite repair
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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’.
KeywordsSaccharopine Neurometabolic Disorder Dicarboxylic Aciduria Pyruvate Carboxylase Deficiency Riboflavin Supplement
l-2-hydroxyglutarate dehydrogenase gene
Work in the authors’ laboratory is supported by the Interuniversity Attraction Pole Programme, Belgian Science Policy (network P6/05), the Fonds de la Recherche Scientifique Médicale, the Actions de Recherche Concertées of the French Community of Belgium, and by a grant of Asco industries. M.V.D.C. is Chercheur Qualifié of the Fonds National de la Recherche Scientifique.
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