Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Academic Medical Center, Amsterdam, The Netherlands.
Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Academic Medical Center, Amsterdam, The Netherlands.
Biochim Biophys Acta Mol Basis Dis. 2018 Mar;1864(3):952-958. doi: 10.1016/j.bbadis.2017.12.032. Epub 2017 Dec 26.
Peroxisomal acyl-CoA oxidases catalyze the first step of beta-oxidation of a variety of substrates broken down in the peroxisome. These include the CoA-esters of very long-chain fatty acids, branched-chain fatty acids and the C27-bile acid intermediates. In rat, three peroxisomal acyl-CoA oxidases with different substrate specificities are known, whereas in humans it is believed that only two peroxisomal acyl-CoA oxidases are expressed under normal circumstances. Only three patients with ACOX2 deficiency, including two siblings, have been identified so far, showing accumulation of the C27-bile acid intermediates. Here, we performed biochemical studies in material from a novel ACOX2-deficient patient with increased levels of C27-bile acids in plasma, a complete loss of ACOX2 protein expression on immunoblot, but normal pristanic acid oxidation activity in fibroblasts. Since pristanoyl-CoA is presumed to be handled by ACOX2 specifically, these findings prompted us to re-investigate the expression of the human peroxisomal acyl-CoA oxidases. We report for the first time expression of ACOX3 in normal human tissues at the mRNA and protein level. Substrate specificity studies were done for ACOX1, 2 and 3 which revealed that ACOX1 is responsible for the oxidation of straight-chain fatty acids with different chain lengths, ACOX2 is the only human acyl-CoA oxidase involved in bile acid biosynthesis, and both ACOX2 and ACOX3 are involved in the degradation of the branched-chain fatty acids. Our studies provide new insights both into ACOX2 deficiency and into the role of the different acyl-CoA oxidases in peroxisomal metabolism.
过氧化物酶体酰基辅酶 A 氧化酶催化各种在过氧化物酶体中分解的底物的β氧化的第一步。这些底物包括长链脂肪酸、支链脂肪酸和 C27 胆汁酸中间产物的 CoA 酯。在大鼠中，已知有三种具有不同底物特异性的过氧化物酶体酰基辅酶 A 氧化酶，而在人类中，据信在正常情况下仅表达两种过氧化物酶体酰基辅酶 A 氧化酶。迄今为止，仅发现了三名 ACOX2 缺乏症患者，包括两名兄弟姐妹，他们表现为 C27 胆汁酸中间产物的积累。在这里，我们对一名新的 ACOX2 缺乏症患者的材料进行了生化研究，该患者的血浆中 C27 胆汁酸水平升高，免疫印迹显示 ACOX2 蛋白表达完全缺失，但成纤维细胞中的植烷酸氧化活性正常。由于植烷酰 CoA 被认为是由 ACOX2 特异性处理的，这些发现促使我们重新研究人类过氧化物酶体酰基辅酶 A 氧化酶的表达。我们首次在正常人类组织中报告了 ACOX3 在 mRNA 和蛋白质水平上的表达。我们对 ACOX1、2 和 3 进行了底物特异性研究，结果表明 ACOX1 负责不同链长的直链脂肪酸的氧化，ACOX2 是唯一参与胆汁酸生物合成的人类酰基辅酶 A 氧化酶，而 ACOX2 和 ACOX3 都参与支链脂肪酸的降解。我们的研究为 ACOX2 缺乏症以及不同酰基辅酶 A 氧化酶在过氧化物酶体代谢中的作用提供了新的见解。
