Mitochondrial phosphatidylethanolamine metabolism

线粒体磷脂酰乙醇胺代谢

• 批准号: 10389237
• 负责人: Steven Michael Claypool
• 金额: $ 3.3万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10389237
• 关键词: Alleles; Alzheimer' s Disease; Biological; Biological Process; Biology; Cancer cell line; Carboxy-Lyases; Cell Proliferation; Chimera organism; Disease; Embryo; Eukaryota; Excision; Genetic Transcription; Goals; Health; Human; Inner mitochondrial membrane; Knowledge; Life; Lipids; Malignant Neoplasms; Mediating; Membrane; Metabolism; Mitochondria; Mitochondrial Proteins; Modeling; Movement; Mus; Pathway interactions; Peptide Hydrolases; Phosphatidylethanolamine; Phosphatidylserines; Phospholipid Metabolism; Phospholipids; Play; Prion Diseases; Role; Temperature; Testing; Tumor Suppressor Proteins; aqueous; enzyme pathway; lipid transport; new therapeutic target; novel; overexpression

The importance of phosphatidylethanolamine (PE) in biology is multi-faceted. PE is typically the second most abundant phospholipid component in biological membranes and thus plays a fundamental role in cellular autonomy and subcellular compartmentalization. In addition, PE is a precursor for other major lipids and is critical for a diverse range of specific biological functions. In eukaryotes, PE synthesis can occur via four separate pathways one of which is performed by phosphatidylserine decarboxylase 1 which resides in the inner mitochondrial membrane. Intriguingly, even though there are four distinct pathways to make PE, deletion of phosphatidylserine decarboxylase 1 is embryonically lethal in mice. Very little is known about regulatory mechanisms that govern flux through the mitochondrial PE pathway. The overarching goal of this application is to begin filling in the numerous gaps in our knowledge about how this essential biosynthetic pathway is regulated. Phosphatidylserine decarboxylase 1 has been traditionally modeled to generate PE by acting on substrate present in the intermembrane space-facing leaflet of the inner membrane. However, recently, it has been suggested that phosphatidylserine decarboxylase 1 can produce PE by acting on substrate present in the outer membrane. An important ramification of this new and yet unsubstantiated in trans model is that it does not require the lipid substrate to traffic across the aqueous intermembrane space. Since lipid trafficking steps represent a means to control access to substrate, knowledge about whether substrate transport across the intermembrane space is required for phosphatidylserine decarboxylase 1 activity, or not, is necessary to establish a framework of putative mechanisms capable of regulating flux through this pathway. The goal of aim 1 is to systematically test the in trans model utilizing a novel topologically inverted chimera of phosphatidylserine decarboxylase 1 whose ability to make PE is absolutely dependent on the movement of substrate across the intermembrane space. Recently, a novel tumor suppressor, LACTB, was discovered that when overexpressed in certain cancer cell lines, reduces cell proliferation and increases cellular differentiation via a mechanism that is at least in part explained by a significant decrease in the levels and function of human phosphatidylserine decarboxylase 1. Importantly, the underlying mechanism responsible for the decrease in phosphatidylserine decarboxylase 1 abundance, which was determined to be post-transcriptionally mediated, was not ascertained. In aim 2, we will continue to exploit a temperature sensitive allele of phosphatidylserine decarboxylase 1 to identify the proteases and define the rules that govern its efficient removal at non- permissive temperature. Ultimately, this information will be used as a guide to unravel how this enzyme and pathway are post-transcriptionally regulated in humans. By obtaining a more comprehensive understanding of mitochondrial PE metabolism, novel therapeutic targets may be identified for those diseases in which PE has been implicated, including Alzheimer's and prion disease, and more recently, cancer.

磷脂酰乙醇胺(PE)在生物学中的重要性是多方面的。体育通常排在第二位 生物膜中丰富的磷脂成分，因此在细胞中起着基础性的作用 自主性和亚细胞区隔。此外，PE是其他主要脂质的前体，并且是 对于一系列特定的生物功能至关重要。在真核生物中，PE的合成可以通过四个途径进行 不同的途径，其中之一是由磷脂酰丝氨酸脱羧酶1执行的，它位于 线粒体膜内层。耐人寻味的是，尽管有四种不同的途径可以使PE，删除 磷脂酰丝氨酸脱羧酶1对小鼠是胚胎致死的。人们对监管机构知之甚少 通过线粒体PE途径控制通量的机制。这个应用程序的主要目标是 开始填补我们关于这一重要的生物合成途径的知识中的大量空白 受监管的。磷脂酰丝氨酸脱羧酶1传统上被模拟为通过作用于 底物存在于膜间面向空间的内膜小叶中。然而，最近，它已经 提示磷脂酰丝氨酸脱羧酶1通过作用于底物而产生PE。 外膜。这一新的但未经证实的TRANS模型的一个重要分支是它确实存在 不需要脂质底物通过水膜间空间进行运输。由于脂类运输步骤 代表了一种控制对底物的访问的方法，关于底物是否通过 膜间隙是磷脂酰丝氨酸脱羧酶1活性所必需的，或者不是必需的 建立一个假定的机制框架，能够通过这一途径调节通量。目标的目标 1是利用一种新的拓扑倒置嵌合体来系统地测试In TRANS模型 磷脂酰丝氨酸脱羧酶1使PE的能力完全依赖于 底物穿过膜间隙。最近，一种新的肿瘤抑制因子LACTB被发现 当在某些癌细胞系中过度表达时，会抑制细胞增殖并促进细胞分化 通过一种机制，这至少部分可以用人的水平和功能的显著下降来解释 磷脂酰丝氨酸脱羧酶1。重要的是，导致 磷脂酰丝氨酸脱羧酶1丰度，被确定为转录后介导， 并未得到确认。在目标2中，我们将继续开发磷脂酰丝氨酸的温度敏感等位基因 脱羧酶1，用于鉴定蛋白酶，并定义管理其在非 允许温度。最终，这一信息将被用作解开这种酶和 途径在人类中是转录后调控的。通过更全面地了解 线粒体PE代谢，有可能成为PE的新治疗靶点 有牵连，包括阿尔茨海默氏症和普里恩病，以及最近的癌症。