Formation of 3-hydroxyglutaric acid in glutaric aciduria type I: in vitro participation of medium chain acyl-CoA dehydrogenase.

3-Hydroxyglutaric acid (3-OH-GA) in urine has been identified as the most reliable diagnostic marker for glutaric aciduria type I (GA I). We showed that hydratation of glutaconyl-CoA to 3-hydroxyglutaryl-CoA, which is subsequently hydrolyzed to 3-OH-GA, is efficiently catalyzed by 3-methylglutaconyl-CoA hydratase (3-MGH). We have now investigated whether mitochondrial acyl-CoA-dehydrogenases can convert glutaryl-CoA to glutaconyl-CoA.

Biochemical characterization of human 3-methylglutaconyl-CoA hydratase and its role in leucine metabolism.

The metabolic disease 3-methylglutaconic aciduria type I (MGA1) is characterized by an abnormal organic acid profile in which there is excessive urinary excretion of 3-methylglutaconic acid, 3-methylglutaric acid and 3-hydroxyisovaleric acid. Affected individuals display variable clinical manifestations ranging from mildly delayed speech development to severe psychomotor retardation with neurological handicap. MGA1 is caused by reduced or absent 3-methylglutaconyl-coenzyme A (3-MG-CoA) hydratase activity within the leucine degradation pathway.

3-Methylglutaconyl-CoA hydratase from Acinetobacter sp.

Acinetobacter strain IVS-B aerobically grows on isovalerate as sole carbon and energy source. Isovalerate is metabolised via isovaleryl-CoA, an intermediate of the oxidative (S)-leucine degradation pathway. A 3-methylglutaconyl-CoA hydratase (EC 4.

Mutations in the AUH gene cause 3-methylglutaconic aciduria type I.

The conversion of 3-methylglutaconyl-CoA to 3-hydroxy-3-methylglutaryl-CoA is the only step in leucine catametabolism yet to be characterized at enzyme and DNA levels. The deficiency of the putative mitochondrial enzyme 3-methylglutaconyl-CoA hydratase associates with the rare organic aciduria 3-methylglutaconic aciduria type I (MGA1), but neither the enzyme nor its gene have been described in any organism. Here we report that human 3-methylglutaconyl-CoA hydratase is identical with a previously described RNA-binding protein (designated AUH) possessing enoyl-CoA hydratase activity.