Characterization of Mammalian Ceramide Synthases

哺乳动物神经酰胺合成酶的表征

基本信息

批准号：
8237460
负责人：
ALFRED Harrison MERRILL
金额：
$ 33.02万
依托单位：
GEORGIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-05-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8237460
关键词：
Abnormal Cell Accounting Acyl Coenzyme A Address Affect Alanine Amides Anabolism Binding Binding Sites Biochemical Biological Biological Process Biology Categories Cell physiology Cell secretion Cells Ceramides Code Complex Data Development Disease Enzymes Fatty Acids Fumonisins Funding Genes Genetic Glycine Goals Grant Hepatocyte Homo Hydroxyl Radical Individual Inherited Intervention Knockout Mice Knowledge Laboratories Length Link Lipoproteins Mammals Maps Mass Spectrum Analysis Metabolism Methods Molecular Mycotoxins N acylation Normal Cell Pathway interactions Physiological Plasma Process Production Proteins Regulation Research Role Serine Site-Directed Mutagenesis Sphingolipids Sphingosine Subcategory Substrate Specificity Technology Tissues Transcript Vertebral column base cytotoxic dihydroceramide desaturase dimer enzyme pathway human disease interest novel pi bond research study sensory neuropathy serine palmitoyltransferase sphinganine sphingosine 1-phosphate stearoyl-coenzyme A

项目摘要

DESCRIPTION (provided by applicant): Ceramides (Cer) are comprised of a sphingoid base and amide-linked fatty acid, and are the backbones of complex sphingolipids as well as modulators of vital cellular processes. In recent years, it has become evident that mammalian tissues contain many different subcategories of Cer, and that the enzymes that form these important compounds are highly selective with respect to the fatty acyl-CoA substrate, but their selectivities for the sphingoid base have not yet been fully defined. Therefore, the overall objective of this grant is to provide a more fundamental and complete understanding of Cer synthases (CerS), their roles in regulating sphingoid base and Cer metabolism, and functions of novel metabolites. A major goal of the research in this grant is to elucidate the pathways for the biosynthesis and turnover of two recently discovered 1-deoxy- and 1-desoxymethyl-sphingoid bases as the backbones, and some of their biological functions (Aim 1). These compounds are made when serine palmitoyltransferase utilizes alanine or glycine instead of serine, and at least one known disease-human sensory neuropathy type 1, HSN1--has been found to result from elevated production of 1-deoxysphinganine (present mainly as the downstream metabolite 1- deoxydihydroCer). Preliminary studies for this proposal have established that production of these alternative categories of sphingolipids is far more common than has been previously appreciated, and the factors that influence their biosynthesis will be identified. Characterization of the CerS will also establish which are responsible for production of particular Cer subspecies, structural features of the enzymes that account for this selectivity, and determine how their activity is influenced by formation of homo- and hetero- dimers (Aim 2). These studies will utilize "lipidomic" mass spectrometry for the sphingolipid analysis because this technology provides information about not only individual molecular subspecies but also for other branches and metabolites. Thus, Aim 3 of the proposal will evaluate "cross-talk" among the different branches and metabolites and provide a integrative explanation for why distinctive subspecies distributions are found in plasma and tissues. Since many of the subspecies of sphingoid bases and Cer have been implicated in inherited and acquired disease, these studies will provide the underlying map of Cer metabolism that will help these processes be understood, and assist in developing more rational strategies for intervention. PUBLIC HEALTH RELEVANCE: Ceramides are modulators of vital cellular processes and have been implicated in inherited and acquired disease. The proposed studies will provide a map of ceramide metabolism that will aid in the understanding of diseases that are caused by aberrant ceramide metabolism, and assist in developing more rational strategies for intervention.

描述（由申请人提供）：神经酰胺（CER）由鞘脂碱和酰胺连接的脂肪酸组成，是复杂的鞘脂的骨架以及重要的细胞过程的调节剂。近年来，哺乳动物组织含有许多不同的CER子类别，并且形成这些重要化合物的酶相对于脂肪酰基-COA底物具有很高的选择性，但它们对脊体碱的选择尚未具有已完全定义。因此，这笔赠款的总体目标是提供对CER合成酶（CERS），它们在调节鞘脂碱和CER代谢中的作用以及新代谢物的功能的更基本和完整的理解。该赠款中该研究的主要目的是阐明两个最近发现的两个最近发现的1-脱氧和1-甲氧基甲基 - 闪细的碱的途径，作为骨架，以及它们的某些生物学功能（AIM 1）。当丝氨酸棕榈酰转移酶使用丙氨酸或甘氨酸而不是丝氨酸时，这些化合物是制成的，至少一种已知的疾病 - 人类感觉神经病1型1型HSN1-被发现是由于1-脱氧丙氨酸的产生而引起的（主要是下降代谢物的下属代谢物。 1-脱氧二氢位）。该提案的初步研究已经确定，这些替代类别的鞘脂的产生比以前所欣赏的要普遍得多，并且将确定影响其生物合成的因素。 CER的表征还将确定负责特定CER亚种的生产，解释这种选择性的酶的结构特征，并确定其活性如何受同型和异性二聚体形成的影响（AIM 2）。这些研究将利用“脂肪组”质谱法进行鞘脂分析，因为该技术不仅提供了有关单个分子亚种，而且提供其他分支和代谢物的信息。因此，该提案的目标3将评估不同分支和代谢产物之间的“跨对词”，并为为什么在血浆和组织中发现独特的亚种分布提供了综合解释。由于许多鞘类碱基和CER的亚种都与遗传和获得的疾病有关，因此这些研究将提供CER代谢的基本图，这些图将有助于理解这些过程，并有助于制定更合理的干预策略。公共卫生相关性：神经酰胺是重要的细胞过程的调节剂，并且与遗传和获得的疾病有关。拟议的研究将提供有关神经酰胺代谢的地图，该图将有助于理解由异常神经酰胺代谢引起的疾病，并有助于制定更理性的干预策略。