Enzymatic characterization of ELOVL1, a key enzyme in very long-chain fatty acid synthesis
Enzymatic characterization of ELOVL1, a key enzyme in very long-chain fatty acid synthesis
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DOI：
10.1016/j.bbalip.2014.12.005
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发表时间：
2015-02-01
影响因子：
4.8
通讯作者：
Kemp, Stephan
中科院分区：
文献类型：
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作者：
Schackmann, Martin J. A.;Ofman, Rob;Kemp, Stephan
X连锁肾上腺脑白质营养不良(X-ALD)是一种由ABCD1基因突变引起的神经代谢性疾病。ABCD1蛋白缺乏会损害过氧化体超长链脂肪酸(VLCFA)的降解，导致细胞质VLCFA-CoA水平增加，VLCFA特异性伸长酶ELOVL1进一步延长VLCFA-CoA水平。在成年期，X-ALD最常见的表现是一种逐渐进行性的脊髓病(肾上腺髓神经病；AMN)，没有任何根治或疾病改善治疗。我们最近发现，苯扎贝特通过抑制ELOVL1减少了VLCFA在X-ALD成纤维细胞中的积聚。尽管在临床试验中，苯扎贝特不能降低X-ALD患者血浆或淋巴细胞中的VLCFA水平，但抑制ELOVL1仍然是一个有吸引力的治疗选择。在这项研究中，我们使用X-ALD成纤维细胞和高表达的HEK293细胞的微粒体部分研究了ELOVL1的动力学特征，并分析了一系列贝特类药物的抑制动力学。我们的数据表明，苯扎贝特和吉非罗齐的辅酶A酯通过特异性抑制ELOVL1来减少链的延长。因此，这些贝特类化合物可以作为开发更有效、更特异的ELOVL1抑制剂的先导化合物。(C)2014爱思唯尔B.V.保留所有权利。
X-linked adrenoleukodystrophy (X-ALD) is a neurometabolic disease that is caused by mutations in the ABCD1 gene. ABCD1 protein deficiency impairs peroxisomal very long-chain fatty acid (VLCFA) degradation resulting in increased cytosolic VLCFA-CoA levels, which are further elongated by the VLCFA-specific elongase, ELOVL1. In adulthood, X-ALD most commonly manifests as a gradually progressive myelopathy (adrenomyeloneuropathy; AMN) without any curative or disease modifying treatments. We recently showed that bezafibrate reduces VLCFA accumulation in X-ALD fibroblasts by inhibiting ELOVL1. Although, in a clinical trial, bezafibrate was unable to lower VLCFA levels in plasma or lymphocytes in X-ALD patients, inhibition of ELOVL1 remains an attractive therapeutic option. In this study, we investigated the kinetic characteristics of ELOVL1 using X-ALD fibroblasts and microsomal fractions from ELOVL1 over-expressing HEK293 cell lines and analyzed the inhibition kinetics of a series of fibrates. Our data show that the CoA esters of bezafibrate and gemfibrozil reduce chain elongation by specifically inhibiting ELOVL1. These fibrates can therefore serve as lead compounds for the development of more potent and more specific inhibitors for ELOVL1. (C) 2014 Elsevier B.V. All rights reserved.