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

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。为了与磷脂、甘油三酯或胆固醇酯结合、延伸、去饱和、b氧化降解或蛋白质酰化，脂肪酸必须首先被激活为辅酶a硫酯。尽管有这种重要的功能，但直到最近才开始研究许多哺乳动物ACSs在代谢中的确切作用。我们根据氨基酸序列相似性将ACSs分为至少6个家族。两个人类和小鼠ACS家族，极长链ACS （VLACS）家族和最近发现的包含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bbb22个碳）的酶。VLCFA是复杂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积累，XALD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氧化降解VLCFA的缺陷和过氧化物酶体中VLCFA活性的降低与XALD的生化病理有关。然而，XALD中存在缺陷的ABCD1基因编码ALDP，这是一种atp结合盒跨膜转运蛋白超家族的过氧化物酶体蛋白，没有VLACS活性。VLACS和BG家族共含有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特定功能。因此，我们建议：1)开发一种新的、普遍适用的ACS检测方法；2)研究人类VLACSs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。

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.