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Mitochondrial phosphatidylethanolamine metabolism

线粒体磷脂酰乙醇胺代谢

基本信息

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
项目类别：
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&apos 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

项目摘要

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。私募股权通常是第二多