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。 PE通常是第二个 生物膜中丰富的磷脂成分，因此在细胞中起着基本作用 自主和亚细胞隔室化。此外，PE是其他主要脂质的前体，是 对于各种特定的生物学功能至关重要。在真核生物中，PE合成可以通过四个 单独的途径之一是由磷脂酰丝氨酸脱羧酶1进行的，它位于 内部线粒体膜。有趣的是，即使有四个不同的途径可以使PE删除 小鼠磷脂酰丝氨酸脱羧酶1的胚胎致死。关于监管的知之甚少 控制通过线粒体PE途径通量的机制。此应用程序的总体目标是 开始填补我们有关这种基本生物合成途径的知识中的众多空白 受监管。传统上已经对磷脂酰丝氨酸脱羧酶1进行了建模，以通过作用在PE上。 底物存在于内膜的膜间空间小叶中。但是，最近它有 有人提出，磷脂酰甲酯脱羧酶1可以通过作用于存在的底物来产生PE 外膜。在跨性别模型中，这种新的却没有确立的重要后果是它确实 不需要脂质底物可以跨膜间空间交通。由于脂质贩运步骤 代表一种控制访问底物的手段，了解底物是否在 磷脂酰丝氨酸脱羧酶1活性是必需的，是否需要膜间空间。 建立一个能够调节通过该途径的通量的假定机制的框架。目标的目标 1是系统地测试使用新颖的拓扑倒置的反式模型 磷脂酰丝氨酸脱羧酶1的能力绝对取决于运动 跨膜间空间的底物。最近，发现一种新型的肿瘤抑制剂Lactb，发现 当在某些癌细胞系中过表达时，减少细胞增殖并增加细胞分化 通过一种至少部分地解释的机制，人类的水平和功能显着降低 磷脂酰丝氨酸脱羧酶1。重要的是，导致减少的基本机制 磷脂酰丝氨酸脱羧酶1的丰度，被确定为转录后介导的， 没有确定。在AIM 2中，我们将继续利用磷脂酰丝氨酸的温度敏感等位基因 脱羧酶1以识别蛋白酶并定义了在非 - 允许温度。最终，这些信息将被用作解开该酶和如何的指南 途径在人类中受到转录后的调节。通过对 线粒体PE代谢，可以确定新的治疗靶标的PE具有的疾病 被暗示，包括阿尔茨海默氏症和prion病，以及最近的癌症。