title: Glutaconyl-CoA is the main toxic agent in glutaryl-CoA dehydrogenase deficiency (glutaric aciduria type I).
abstract: Despite early diagnosis and treatment, 35% of the patients with glutaric aciduria type I (GA I) develop severe neurologic damage. Glutaric acid and 3-hydroxyglutaric acid have been suspected to cause neurodegeneration. Lately, this has been questioned, however. We postulate that glutaconyl Coenzyme A (glutaconyl-CoA) is responsible for brain damage. Chemically, glutaconyl-CoA is an analogue of acrylyl-CoA, the parent substance of the extremely reactive class of acrylates. It is expected to react spontaneously with sulfhydryl groups, thus modifying membranes, disturbing enzyme functions and trapping glutathione. Enhanced production of glutaconyl-CoA together with lack of glutathione precipitates brain damage. Such a mechanism is supported by three findings. (1) The addition product of glutaconyl-CoA to cysteine is present in small amounts in normal human urine. (2) Reaction of methacrylyl-CoA with free sulfhydryl groups has been reported previously in a patient with 3-hydroxyisobutyryl CoA deacylase deficiency. (3) Glutathione has been found to be decreased in homozygous glutaryl-CoA dehydrogenase-deficient knock-out mice.
authors.affiliation: Stoffwechsellabor, Zentrum für Kinderheilkunde- und Jugendmedizin, Universitätsklinikum Freiburg, Mathildenstr. 1, D-79106 Freiburg, Germany.
authors.forename: Willy
authors.initials: W
authors.lastname: Lehnert
authors.forename: Jörn Oliver
authors.initials: JO
authors.lastname: Sass
mesh_terms: D000214:Acyl Coenzyme A / Q000494:pharmacology*; D000592:Amino Acid Metabolism, Inborn Errors / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D003545:Cysteine / Q000737:chemistry; D050770:Glutaryl-CoA Dehydrogenase; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008956:Models, Chemical; D008962:Models, Theoretical; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000172:deficiency*
chemical_list: D000214:Acyl Coenzyme A; C032423:glutaconyl-coenzyme A; D044925:Oxidoreductases Acting on CH-CH Group Donors; D050770:Glutaryl-CoA Dehydrogenase; D005978:Glutathione; D003545:Cysteine