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（由申请人提供）：酰基-COA合成酶（ACS）在脂肪酸代谢中占中心位置。为了掺入磷脂，甘油三酸酯或胆固醇酯，伸长，去饱和，通过B氧化或蛋白质的酰化降解，必须首先将脂肪酸激活至其CoA Thioester。尽管有这种重要功能，但直到最近才开始研究众多哺乳动物ACS的代谢中的精确作用。我们通过氨基酸序列相似性将ACS分组为至少六个家族。两个人和小鼠ACS家族，非常长链ACS（VLAC）家族和一个最近发现的ACS家族，其中包括BG基因（在果蝇中突变的“ BubbleGum”中突变）含有能够激活非常长链脂肪酸（VLCFA;含有> 22 Carbons）的酶。 VLCFA是复杂脂质的重要组成部分，尤其是在大脑中，维持VLCFA稳态对正常健康至关重要。因此，通过上述任何途径控制VLCFA的命运的酶都是至关重要的。 VLCFA积聚在血浆和X连锁肾上腺素肌营养不良（XALD）的患者的组织中，这是一种严重的，通常是致命的神经退行性疾病。通过过氧化物酶体B氧化和过氧化物酶体中VLACS活性降解的VLCFA降解与XALD的生化病理有关。然而，XALD中的基因ABCD1中有缺陷，编码ALDP，ALDP是ATP结合盒的过氧化物酶体蛋白质蛋白，它没有VLACS活性。 VLAC和BG家族总共包含8种酶。为了了解总体VLCFA稳态，我们必须了解每种酶的特定功能。因此，我们建议：1）开发一种新颖且通常适用的ACS分析，2）研究人VLACS的特定生物学作用，以及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引导到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XALD中属于VLACS或BG家族的酶的作用。