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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）由鞘碱和酰胺连接脂肪酸组成，是复杂鞘脂的骨干，也是重要细胞过程的调节剂。近年来，很明显，哺乳动物组织中含有许多不同亚类的Cer，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，但它们对鞘基的选择性尚未完全确定。因此，本资助的总体目标是对Cer合成酶（Cer）及其在调节鞘碱和Cer代谢中的作用，以及新型代谢物的功能提供更基本和完整的了解。本研究的一个主要目标是阐明最近发现的两种作为骨干的1-脱氧和1-去氧甲基-鞘碱的生物合成和转换途径，以及它们的一些生物学功能（目的1）。当丝氨酸棕榈酰基转移酶使用丙氨酸或甘氨酸而不是丝氨酸时，这些化合物就会产生，并且至少有一种已知的疾病-人类感觉神经病变1型HSN1-已被发现是由于1-脱氧鞘氨酸（主要作为下游代谢物1-脱氧二氢氢）的产生升高引起的。本提案的初步研究已经确定，这些替代类别的鞘脂的生产比以前所认识的要普遍得多，并且将确定影响其生物合成的因素。Cer的表征还将确定哪些负责特定Cer亚种的产生，解释这种选择性的酶的结构特征，并确定它们的活性如何受到同源和异源二聚体形成的影响（目标2）。这些研究将利用“脂质组学”质谱法进行鞘脂分析，因为这项技术不仅提供了单个分子亚种的信息，还提供了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不同的亚种分布提供一个综合解释。由于鞘基和Cer的许多亚种与遗传和获得性疾病有关，这些研究将提供Cer代谢的基本图谱，有助于了解这些过程，并有助于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）

Characterization of mutant serine palmitoyltransferase 1 in LY-B cells.

LY-B 细胞中突变丝氨酸棕榈酰转移酶 1 的表征。

DOI：
10.1007/s11745-009-3316-4
发表时间：
2009
期刊：
Lipids
影响因子：
1.9
作者：
Momin,AminA;Park,Hyejung;Allegood,JeremyC;Leipelt,Martina;Kelly,SamuelL;MerrillJr,AlfredH;Hanada,Kentaro
通讯作者：
Hanada,Kentaro

Development of pheochromocytoma in ceramide synthase 2 null mice.

DOI：
10.1530/erc-15-0058
发表时间：
2015-08
期刊：
Endocrine-related cancer
影响因子：
3.9
作者：
Park WJ;Brenner O;Kogot-Levin A;Saada A;Merrill AH Jr;Pewzner-Jung Y;Futerman AH
通讯作者：
Futerman AH

Critical Role for Very-Long Chain Sphingolipids in Invariant Natural Killer T Cell Development and Homeostasis.

DOI：
10.3389/fimmu.2017.01386
发表时间：
2017
期刊：
Frontiers in immunology
影响因子：
7.3
作者：
Saroha A;Pewzner-Jung Y;Ferreira NS;Sharma P;Jouan Y;Kelly SL;Feldmesser E;Merrill AH Jr;Trottein F;Paget C;Lang KS;Futerman AH
通讯作者：
Futerman AH

Mammalian ceramide synthases.