Inhibition of brain glutamate decarboxylase by glutarate, glutaconate, and β-Hydroxyglutarate: Explanation of the symptoms in glutaric aciduria?

摘要: Glutaric aciduria is a disorcer of lysine, tryptophan, and hydroxylysine metabolism characterized by intermittent metabolic acidemia, dystonia, athetosis mental retardation. It due to recessively inherited deficiency glutaryl-CoA dehydrogeanse, the enzyme(s) which catalyze dehydrogenation glutaconyl-CoA decarboxylation latter crotonyl-CoA. Abnormal quantities glutaric, beta-hydroxyglutaric, glutaconic acids are found in urine these patients. The nature movement disorder prompted study effects abnormally excreted metabolites on brain glutamate decarboxylase, an enzyme implicated pathogenesis Huntington's chorea. Glutamate decarboxylase activity was examined rat rabbit acetone powders, stabilized with pyridoxal phosphate glutathione. Glutarate, beta-hydroxyglutarate, glutaconate were competitive inhibitors this emzyme, Ki values being 1.3 X 10(-3) mol/l, 2.5 10(-4) respectively. This inhibition may explain neurological accompaniments syndrome.