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

• 批准号: 6849795
• 负责人: Paul A. WATKINS
• 金额: $ 34.2万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-02-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6849795
• 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

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）：酰基辅酶A合成酶（ACS）在脂肪酸代谢中占据中心位置。为了掺入磷脂、甘油三酯或胆固醇酯、延长、去饱和、通过β-氧化降解或蛋白质的酰化，脂肪酸必须首先活化成其CoA硫酯。尽管有这种重要的功能，只是最近才开始研究许多哺乳动物ACS在代谢中的确切作用。我们已经分组ACS的氨基酸序列相似性，至少有六个家庭。两个人类和小鼠ACS家族，极长链ACS（VLACS）家族和最近发现的包括BG基因（在果蝇突变体“泡泡糖”中突变）的ACS家族含有能够激活极长链脂肪酸（VLCFA;含有>22个碳）的酶。VLCFA是复合脂质的重要组成部分，特别是在大脑中，维持VLCFA的稳态对正常健康至关重要。因此，通过上述任何途径控制VLCFA命运的酶是至关重要的。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蓄积，XALD是一种严重的、通常致命的神经退行性疾病。通过过氧化物酶体b-氧化的VLCFA降解缺陷和过氧化物酶体中VLACS活性降低与XALD的生化病理学有关。然而，在XALD，ABCD 1，基因缺陷，编码ALDP，过氧化物酶体蛋白的ATP结合盒跨膜转运蛋白超家族，没有VLACS活动。VLACS和BG家族总共含有8种酶。为了了解整体VLCFA稳态，我们必须了解这些酶中每一种的具体功能。因此，我们建议：1）开发一种新的和普遍适用的ACS测定法，2）研究人VLACS的特定生物学作用，3）表征BG 1敲除小鼠并评估BG 1在XALD中的作用。这些研究的结果将对我们理解脂肪酸如何进入特定的代谢途径产生重大影响。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。