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

The FEBS Journal
Matthias MackJohannes Zschocke

Abstract

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. The human AUH gene has been reported to encode for a bifunctional enzyme with both RNA-binding and enoyl-CoA-hydratase activity. In addition, it was shown that mutations in the AUH gene are linked to MGA1. Here we present kinetic data of the purified gene product of AUH using different CoA-substrates. The best substrates were (E)-3-MG-CoA (V(max) = 3.9 U.mg(-1), K(m) = 8.3 microM, k(cat) = 5.1 s(-1)) and (E)-glutaconyl-CoA (V(max) = 1.1 U.mg(-1), K(m) = 2.4 microM, k(cat) = 1.4 s(-1)) giving strong evidence that the AUH gene encodes for the major human 3-MG-CoA hydratase in leucine degradation. Based on these results, a new assay for AUH activity in fibroblast homogenates was developed. T...Continue Reading

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Citations

Mar 7, 2014·Nucleic Acids Research·Tara R RichmanAleksandra Filipovska
Aug 17, 2011·Biochemical Pharmacology·Paula B M LuísMargarida F B Silva
Oct 3, 2008·Proteins·Kazuki KurimotoShigeyuki Yokoyama
Aug 16, 2011·Molecular Genetics and Metabolism·Saadet Mercimek-MahmutogluBrett Casey
Apr 4, 2017·Molecular and Biochemical Parasitology·Mariana Leão de Lima SteinSergio Schenkman
Oct 11, 2013·Journal of the American Heart Association·Jianhai DuYang Shi
May 1, 2008·Proteomics. Clinical Applications·Frank GillardonBastian Hengerer
Mar 23, 2017·Amino Acids·María M Adeva-AndanyCristina Sixto-Leal
Apr 20, 2016·Journal of Inherited Metabolic Disease·Nikita Ikon, Robert O Ryan
May 18, 2021·Frontiers in Cell and Developmental Biology·Tim Baldensperger, Marcus A Glomb
Aug 20, 2021·Clinica Chimica Acta; International Journal of Clinical Chemistry·Dylan E JonesRobert O Ryan
Dec 9, 2021·The FEBS Journal·Dylan E JonesRobert O Ryan

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