Ferdinandusse S, Denis S, IJlst L, Dacremont G, Waterham H R, Wanders R J
Departments of Clinical Chemistry, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
J Lipid Res. 2000 Nov;41(11):1890-6.
alpha-Methylacyl-CoA racemase plays an important role in the beta-oxidation of branched-chain fatty acids and fatty acid derivatives because it catalyzes the conversion of several (2R)-methyl-branched-chain fatty acyl-CoAs to their (S)-stereoisomers. Only stereoisomers with the 2-methyl group in the (S)-configuration can be degraded via beta-oxidation. Patients with a deficiency of alpha-methylacyl-CoA racemase accumulate in their plasma pristanic acid and the bile acid intermediates di- and trihydroxycholestanoic acid, which are all substrates of the peroxisomal beta-oxidation system. Subcellular fractionation experiments, however, revealed that both in humans and rats alpha-methylacyl-CoA racemase is bimodally distributed to both the peroxisome and the mitochondrion. Our findings show that the peroxisomal and mitochondrial enzymes are produced from the same gene and that, as a consequence, the bimodal distribution pattern must be the result of differential targeting of the same gene product. In addition, we investigated the physiological role of the enzyme in the mitochondrion. Both in vitro studies with purified heterologously expressed protein and in vivo studies in fibroblasts of patients with an alpha-methylacyl-CoA racemase deficiency revealed that the mitochondrial enzyme plays a crucial role in the mitochondrial beta-oxidation of the breakdown products of pristanic acid byconverting (2R,6)-dimethylheptanoyl-CoA to its (S)-stereoisomer.
α-甲基酰基辅酶A消旋酶在支链脂肪酸和脂肪酸衍生物的β-氧化过程中发挥着重要作用，因为它催化多种(2R)-甲基支链脂肪酰基辅酶A转化为其(S)-立体异构体。只有2-甲基处于(S)-构型的立体异构体才能通过β-氧化进行降解。α-甲基酰基辅酶A消旋酶缺乏的患者血浆中会积累植烷酸以及胆汁酸中间体二羟基胆甾烷酸和三羟基胆甾烷酸，这些都是过氧化物酶体β-氧化系统的底物。然而，亚细胞分级分离实验表明，在人类和大鼠中，α-甲基酰基辅酶A消旋酶都以双峰形式分布于过氧化物酶体和线粒体中。我们的研究结果表明，过氧化物酶体和线粒体中的酶由同一基因产生，因此，这种双峰分布模式必定是同一基因产物不同靶向作用的结果。此外，我们还研究了该酶在线粒体中的生理作用。对纯化的异源表达蛋白进行的体外研究以及对α-甲基酰基辅酶A消旋酶缺乏患者成纤维细胞进行的体内研究均表明，线粒体中的该酶通过将(2R,6)-二甲基庚酰辅酶A转化为其(S)-立体异构体，在植烷酸分解产物的线粒体β-氧化过程中发挥关键作用。
