Mitochondrial phosphatidylethanolamine metabolism

线粒体磷脂酰乙醇胺代谢

• 批准号: 10303279
• 负责人: Steven Michael Claypool
• 金额: $ 1.29万
• 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 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10303279
• 关键词: Active Sites; Address; Alleles; Alzheimer' s Disease; Biological; Biological Process; Biology; Cancer cell line; Carboxy-Lyases; Carrier Proteins; Cell Proliferation; Cell physiology; Cells; Chimera organism; Complement; Disease; Embryo; Enzymes; Eukaryota; Event; Excision; Face; Funding; Genetic Transcription; Goals; Health; Homeostasis; Human; Human Pathology; Impairment; In Vitro; Inner mitochondrial membrane; Knowledge; Life; Life Cycle Stages; Link; Lipid Bilayers; Lipids; Malignant Neoplasms; Mediating; Membrane; Metabolism; Mitochondria; Mitochondrial Membrane Protein; Mitochondrial Proteins; Modeling; Monitor; Movement; Mus; Pathway interactions; Peptide Hydrolases; Phenotype; Phosphatidylethanolamine; Phosphatidylserines; Phospholipid Metabolism; Phospholipids; Play; Prion Diseases; Production; Proteins; Quality Control; Regulation; Role; Route; Site; Structure; Temperature; Testing; Tumor Suppressor Proteins; Yeasts; aqueous; base; enzyme pathway; in vivo; lipid transport; new therapeutic target; novel; overexpression; trafficking

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通常是第二大 磷脂是生物膜中丰富的磷脂成分，因此在细胞内起着重要作用。 自主性和亚细胞区室化。此外，PE是其他主要脂质的前体， 对多种特定生物功能至关重要。在真核生物中，PE合成可以通过四个途径进行。 分离的途径，其中之一是由磷脂酰丝氨酸脱羧酶1，它存在于 线粒体内膜有趣的是，尽管有四种不同的途径来制造PE， 磷脂酰丝氨酸脱羧酶1在小鼠胚胎中是致命的。对监管知之甚少 通过线粒体PE途径控制流量的机制。此应用程序的首要目标是 开始填补我们关于这种重要的生物合成途径是如何 监管.磷脂酰丝氨酸脱羧酶1传统上被建模为通过作用于 在内膜的面向膜间空间的小叶中存在的底物。然而，最近， 已经提出磷脂酰丝氨酸脱羧酶1可以通过作用于存在于磷脂酰丝氨酸脱羧酶1中的底物来产生PE。 外膜这个新的，但未经证实的反式模型的一个重要分支是，它确实 不需要脂质底物穿过含水的膜间隙。由于脂质运输步骤 表示控制对衬底的访问的手段，关于衬底是否穿过衬底传输的知识， 磷脂酰丝氨酸脱羧酶1活性所需的膜间隙，或不是必需的， 建立一个框架的推定机制能够调节流量通过这一途径。aim的目标 1是系统地测试反式模型，利用一种新的拓扑反转嵌合体， 磷脂酰丝氨酸脱羧酶1，其产生PE的能力完全依赖于 基质穿过膜间空间。最近，发现了一种新的肿瘤抑制因子LACTB， 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 通过一种机制，至少部分地解释为人类免疫缺陷病毒的水平和功能的显著下降， 磷脂酰丝氨酸脱羧酶1.重要的是，造成死亡率下降的根本机制 磷脂酰丝氨酸脱羧酶1丰度，其被确定为转录后介导的， 没有得到确认。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，以确定蛋白酶，并确定规则，管理其有效的去除在非- 允许温度最终，这些信息将被用来指导解开这种酶和 在人类中是转录后调节的。通过更全面地了解 线粒体PE代谢，新的治疗靶点可以确定为那些疾病，其中PE具有 包括老年痴呆症和朊病毒病，以及最近的癌症。