Peters Verena, Morath Marina, Mack Matthias, Liesert Michael, Buckel Wolfgang, Hoffmann Georg F, Vockley Jerry, Ghisla Sandro, Zschocke Johannes
Center für Paediatric and Adolescent Medicine University of Heidelberg Germany.
Institut für Technische Mikrobiologie Hochschule Mannheim Germany.
JIMD Rep. 2019 Mar 26;47(1):30-34. doi: 10.1002/jmd2.12026. eCollection 2019 May.
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 of glutaryl-CoA was found for MCAD (0.12 ± 0.01 second) 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 (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.
尿中的3-羟基戊二酸（3-OH-GA）已被确定为I型戊二酸血症（GA I）最可靠的诊断标志物。我们发现，戊烯二酰辅酶A水合生成3-羟基戊二酰辅酶A，随后水解为3-OH-GA，这一过程由3-甲基戊烯二酰辅酶A水合酶（3-MGH）高效催化。我们现在研究了线粒体酰基辅酶A脱氢酶是否能将戊二酰辅酶A转化为戊烯二酰辅酶A。短链酰基辅酶A脱氢酶（SCAD）、中链酰基辅酶A脱氢酶（MCAD）和长链酰基辅酶A脱氢酶（LCAD）均接受戊二酰辅酶A作为底物。MCAD对戊二酰辅酶A的最高催化效率（0.12±0.01秒）分别比LCAD和SCAD高约26倍和52倍。MCAD对戊二酰辅酶A的催化周转率约为其天然底物辛酰辅酶A的1.5%。尽管催化效率较高（高于600μM）且周转率较低，但MCAD与3-MGH共同作用氧化戊二酰辅酶A可以解释GA I患者尿液中3-OH-GA的浓度。
