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：
8841741
负责人：
ALFRED Harrison MERRILL
金额：
$ 31.7万
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 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8841741
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.

描述（由申请人提供）：神经酰胺 (Cer) 由鞘氨醇碱和酰胺连接的脂肪酸组成，是复杂鞘脂的主链以及重要细胞过程的调节剂。近年来，越来越明显的是，哺乳动物组织含有许多不同的 Cer 亚类，并且形成这些重要化合物的酶对脂肪酰基辅酶 A 底物具有高度选择性，但它们对鞘氨醇碱的选择性尚未确定。已被完全定义。因此，这项资助的总体目标是提供对 Cer 合酶 (CerS)、它们在调节鞘氨醇碱和 Cer 代谢中的作用以及新型代谢物的功能的更基本和完整的了解。本次资助研究的一个主要目标是阐明最近发现的两种作为骨架的 1-脱氧-和 1-脱氧甲基-鞘氨醇碱基的生物合成和周转途径，以及它们的一些生物学功能（目标 1）。这些化合物是当丝氨酸棕榈酰转移酶利用丙氨酸或甘氨酸代替丝氨酸时产生的，并且至少一种已知的疾病 - 1 型人类感觉神经病 HSN1 - 已被发现是由 1-脱氧二氢鞘氨醇（主要作为下游代谢物存在）的产生增加引起的1-脱氧二氢Cer)。该提案的初步研究表明，这些替代类别的鞘脂的生产比以前认识的要普遍得多，并且将确定影响其生物合成的因素。 CerS 的表征还将确定哪些酶负责产生特定的 Cer 亚种、解释这种选择性的酶的结构特征，并确定同二聚体和异二聚体的形成如何影响它们的活性（目标 2）。这些研究将利用“脂质组学”质谱法进行鞘脂分析，因为该技术不仅提供有关单个分子亚种的信息，还提供有关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物之间的“串扰”，并为为什么在血浆和组织中发现独特的亚种分布提供综合解释。由于鞘氨醇碱和 Cer 的许多亚种与遗传性和获得性疾病有关，因此这些研究将提供 Cer 代谢的基本图谱，这将有助于理解这些过程，并协助制定更合理的干预策略。

项目成果

期刊论文数量（22）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A critical role for ceramide synthase 2 in liver homeostasis: I. alterations in lipid metabolic pathways.

神经酰胺合酶 2 在肝脏稳态中的关键作用：I. 脂质代谢途径的改变。

DOI：
发表时间：
2010-04-02
期刊：
影响因子：
0
作者：
Pewzner;Park, Hyejung;Laviad, Elad L;Silva, Liana C;Lahiri, Sujoy;Stiban, Johnny;Erez;Brügger, Britta;Sachsenheimer, Timo;Wieland, Feli;Prieto, Manuel;Merrill Jr, Alfred H;Futerman, Anthony H
通讯作者：
Futerman, Anthony H

The role of the ceramide acyl chain length in neurodegeneration: involvement of ceramide synthases.

神经酰胺酰基链长度在神经变性中的作用：神经酰胺合酶的参与。

DOI：
发表时间：
2010-12
期刊：
影响因子：
3.5
作者：
Ben;Futerman, Anthony H
通讯作者：
Futerman, Anthony H

Characterization of ceramide synthase 2: tissue distribution, substrate specificity, and inhibition by sphingosine 1-phosphate.

神经酰胺合酶 2 的表征：组织分布、底物特异性和 1-磷酸鞘氨醇的抑制。

DOI：
发表时间：
2008-02-29
期刊：
影响因子：
0
作者：
Laviad, Elad L;Albee, Lee;Pankova;Epstein, Sharon;Park, Hyejung;Merrill Jr, Alfred H;Futerman, Anthony H
通讯作者：
Futerman, Anthony H

Ablation of ceramide synthase 2 strongly affects biophysical properties of membranes.

神经酰胺合酶 2 的消除会强烈影响膜的生物物理特性。

DOI：
发表时间：
2012-03
期刊：
影响因子：
6.5
作者：
Silva, Liana C;Ben David, Oshrit;Pewzner;Laviad, Elad L;Stiban, Johnny;Bandyopadhyay, Sibali;Merrill Jr, Alfred H;Prieto, Manuel;Futerman, Anthony H
通讯作者：
Futerman, Anthony H

Encephalopathy caused by ablation of very long acyl chain ceramide synthesis may be largely due to reduced galactosylceramide levels.

由极长酰基链神经酰胺合成的消除引起的脑病可能很大程度上是由于半乳糖苷神经酰胺水平降低。

DOI：
发表时间：
2011-08-26
期刊：
影响因子：
0
作者：
Ben;Pewzner;Brenner, Ori;Laviad, Elad L;Kogot;Weissberg, Itai;Biton, Inbal E;Pienik, Reut;Wang, Elaine;Kelly, Samuel;Alroy, Joseph;Raas;Friedman, Alon;Brügger, Britta;Merrill Jr, Alfr
通讯作者：
Merrill Jr, Alfr