XALD: Role of Very Long Chain Fatty Acyl-CoA Synthetases

XALD：超长链脂肪酰辅酶A合成酶的作用

基本信息

批准号：
7012166
负责人：
Paul A. WATKINS
金额：
$ 33.4万
依托单位：
HUGO W. MOSER RES INST KENNEDY KRIEGER
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-02-01 至 2008-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7012166
关键词：
acyl coA adrenoleukodystrophy clinical research disease /disorder model enzyme activity enzyme mechanism fatty acid metabolism fatty acid synthase genetically modified animals human genetic material tag human tissue laboratory mouse laboratory rat long chain fatty acid phenotype sex linked trait technology /technique development tissue /cell culture

项目摘要

DESCRIPTION (provided by applicant): Acyl-CoA synthetases (ACS) occupy a central position in fatty acid metabolism. For incorporation into phospholipids, triglycerides, or cholesterol esters, elongation, desaturation, degradation by b-oxidation, or acylation of proteins, a fatty acid must first be activated to its CoA thioester. Despite this vital function, only recently have the precise roles in metabolism of the numerous mammalian ACSs begun to be investigated. We have grouped ACSs by amino acid sequence similarity into at least six families. Two human and mouse ACS families, the very long-chain ACS (VLACS) family and a recently discovered ACS family that includes the BG gene (mutated in the fruit fly mutant "bubblegum") contain enzymes capable of activating very long-chain fatty acids (VLCFA; containing >22 carbons). VLCFA are essential components of complex lipids, particularly in the brain, and maintenance of VLCFA homeostasis is critical to normal health. Thus, enzymes that control the fate of VLCFA by any of the pathways noted above are of central importance. VLCFA accumulate in plasma and tissues of patients with X-linked adrenoleukodystrophy (XALD), a severe, often fatal neurodegenerative disorder. Defective VLCFA degradation via peroxisomal b-oxidation and decreased VLACS activity in peroxisomes have been implicated in the biochemical pathology of XALD. However, the gene defective in XALD, ABCD1, encodes ALDP, a peroxisomal protein of the ATP-binding cassette transmembrane transporter superfamily that has no VLACS activity. The VLACS and BG families contain a total of 8 enzymes. To understand overall VLCFA homeostasis, we must therefore understand the specific function of each of these enzymes. Therefore, we propose: 1) to develop a novel and generally applicable ACS assay, 2) to investigate the specific biological roles of human VLACSs, and 3) to characterize the BG1 knockout mouse and to assess the role of BG1 in XALD. Results of these studies will have a significant impact on our understanding of how fatty acids are channeled into specific metabolic pathways. Furthermore, they will facilitate elucidation of the role of enzymes belonging to the VLACS or BG families in XALD.

描述（申请人提供）：酰基辅酶A合成酶（ACS）在脂肪酸代谢中占据中心地位。为了掺入磷脂、甘油三酯或胆固醇酯、延伸、去饱和、通过 b-氧化降解或蛋白质酰化，脂肪酸必须首先被活化为其 CoA 硫酯。尽管具有这一重要功能，但直到最近才开始研究众多哺乳动物 ACS 在新陈代谢中的确切作用。我们根据氨基酸序列相似性将 ACS 分为至少六个家族。两个人类和小鼠 ACS 家族，即超长链 ACS (VLACS) 家族和最近发现的包含 BG 基因（在果蝇突变体“bubblegum”中突变）的 ACS 家族，均含有能够激活超长链脂肪酸的酶（VLCFA；含有 >22 个碳）。 VLCFA 是复杂脂质的重要组成部分，尤其是在大脑中，维持 VLCFA 稳态对于正常健康至关重要。因此，通过上述任何途径控制 VLCFA 命运的酶至关重要。 VLCFA 在 X 连锁肾上腺脑白质营养不良 (XALD) 患者的血浆和组织中积聚，XALD 是一种严重且往往致命的神经退行性疾病。 XALD 的生化病理学涉及过氧化物酶体 b 氧化导致的 VLCFA 降解缺陷和过氧化物酶体中 VLACS 活性的降低。然而，XALD 缺陷基因 ABCD1 编码 ALDP，一种 ATP 结合盒跨膜转运蛋白超家族的过氧化物酶体蛋白，不具有 VLACS 活性。 VLACS 和 BG 家族总共包含 8 种酶。因此，为了了解 VLCFA 的整体稳态，我们必须了解每种酶的具体功能。因此，我们建议：1）开发一种新颖且普遍适用的 ACS 测定，2）研究人类 VLACS 的特定生物学作用，3）表征 BG1 敲除小鼠并评估 BG1 在 XALD 中的作用。这些研究的结果将对我们对脂肪酸如何进入特定代谢途径的理解产生重大影响。此外，它们将有助于阐明属于 VLACS 或 BG 家族的酶在 XALD 中的作用。