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

描述(申请人提供)：酰辅酶A合成酶(ACS)在脂肪酸代谢中占有中心地位。为了与磷脂、甘油三酯或胆固醇酯结合，伸长、脱饱和、b氧化降解或蛋白质的酰化，脂肪酸必须首先活化为其辅酶A硫代酯。尽管具有这一重要功能，但直到最近才开始研究大量哺乳动物ACSS在新陈代谢中的确切作用。我们根据氨基酸序列的相似性将ACSS分成至少六个家族。人类和小鼠的两个ACS家族，超长链ACS(VLACS)家族和最近发现的包括BG基因的ACS家族(在果蝇突变体“泡泡糖”中突变)含有能够激活超长链脂肪酸(VLCFA；含有~gt；22碳)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的动态平衡对正常健康至关重要。因此，通过上述任何一种途径控制VLCFA命运的酶是至关重要的。VLCFA积聚在X连锁肾上腺脑白质营养不良(XALD)患者的血浆和组织中，XALD是一种严重的、通常是致命的神经退行性疾病。过氧化体b氧化导致的VLCFA降解缺陷和过氧化体中VLACS活性降低与XALD的生化病理有关。然而，XALD中存在缺陷的基因ABCD1编码ALDP，这是一种没有VLACS活性的ATP结合盒跨膜转运蛋白超家族的过氧体蛋白。VLACS和BG家族共含有8种酶。因此，为了了解VLCFA的整体动态平衡，我们必须了解每种酶的特定功能。因此，我们建议：1)建立一种新的、普遍适用的急性冠脉综合征检测方法；2)研究人类VLACSs的特定生物学作用；3)鉴定Bg1基因敲除小鼠，并评估Bg1基因在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.