JIMD Reports (May 2019)

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

  • Verena Peters,
  • Marina Morath,
  • Matthias Mack,
  • Michael Liesert,
  • Wolfgang Buckel,
  • Georg F. Hoffmann,
  • Jerry Vockley,
  • Sandro Ghisla,
  • Johannes Zschocke

DOI
https://doi.org/10.1002/jmd2.12026
Journal volume & issue
Vol. 47, no. 1
pp. 30 – 34

Abstract

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Abstract 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. Short‐chain acyl‐CoA dehydrogenase (SCAD), medium‐chain acyl‐CoA dehydrogenase (MCAD), and long‐chain acyl‐CoA dehydrogenase (LCAD) accepted glutaryl‐CoA as a substrate. The highest kcat of glutaryl‐CoA was found for MCAD (0.12 ± 0.01 second−1) and was about 26‐fold and 52‐fold higher than those of LCAD and SCAD, respectively. The turnover of MCAD for glutaryl‐CoA was about 1.5% of that of its natural substrate octanoyl‐CoA. Despite high Km (above 600 μM) and low turnover rate, the oxidation of glutaryl‐CoA by MCAD in combination with 3‐MGH could explain the urinary concentration of 3‐OH‐GA in GA I patients.

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