Acyl-CoA Synthetase: Structure, Function and Regulation

酰基辅酶 A 合成酶：结构、功能和调节

基本信息

批准号：
8850425
负责人：
Rosalind Anne Coleman
金额：
$ 30.94万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-04-15 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8850425
关键词：
ASCL1 gene Acyl Coenzyme A Acyltransferase Address Adipose tissue Atherosclerosis Carbohydrates Carnitine Carnitine Acyltransferases Cells Coenzyme A Ligases Complex Cultured Cells Data Development Diabetes Mellitus Dietary intake Eicosanoid Production Eicosanoids Endoplasmic Reticulum Energy-Generating Resources Enzymes Fatty Acids Fatty Liver Fatty acid glycerol esters Funding Gene Expression Gluconeogenesis Glucose Hand Heart Heart Hypertrophy Hepatocyte Hypertrophy Hypoglycemia Inflammation Inflammatory Insulin Insulin Resistance Knockout Mice Knowledge Learning Ligands Lipids Liver Location Mediating Membrane Messenger RNA Metabolic Metabolic Pathway Metabolic syndrome Metabolism Mitochondria Mus Myocardium Myopathy Nuclear Nutrition Disorders Obesity Organ Outer Mitochondrial Membrane Pathway interactions Peripheral Phospholipids Phosphorylation Polyunsaturated Fatty Acids Production Protein Isoforms Proteins Regulation Signal Transduction Skeletal Muscle Source Structure Thermogenesis Tissues Triglycerides adipocyte differentiation arachidonate base cost human FRAP1 protein insulin signaling lipid biosynthesis lipid metabolism long chain fatty acid oxidation preference response skeletal transcription factor

项目摘要

DESCRIPTION (provided by applicant): Dietary intake of excess fat or carbohydrate results in increased synthesis and storage of triacylglycerol (TAG). The long-chain fatty acids (FA) that contribute to TAG synthesis must be first converted to acyl-CoAs by long-chain acyl-CoA synthetase (ACSL). Because acyl-CoAs lie at a branch-point of storage and mitochondrial ¿-oxidation, the fate of the acyl-CoAs formed may contribute to, or counteract, nutritional disorders related to increased TAG storage like obesity, fatty liver, atherosclerosis, and diabetes. We hypothesize that 1) ACSL1 is able to direct FA towards ¿-oxidation in highly oxidative tissues because the enzyme interacts with carnitine acyltranferase to hand off its acyl-CoA product; 2) that the function of ACSL1 differs in liver because at least 50% of the protein is present on the endoplasmic reticulum where it interacts with glycerolipid acyltransferases; and 3) that the mechanism for these differences lies both in the membrane association and phosphorylation status of ACSL1. Further, we propose that tissue use of glucose rather than FA as a fuel source is not without cost, and that the metabolic and functional problems arising from this use may be dangerous for organ function and insulin signaling. We further hypothesize, in keeping with the proposition that each ACSL directs FA towards a specific fate, that the ACSL4 isoform functions to regulate the entry of arachidonate into pathways of phospholipid synthesis versus eicosanoid formation. Our studies will address critical gaps in our knowledge about the metabolic fates of FA as substrates for complex lipid formation, as metabolic fuels, as precursors for eicosanoid signaling, as regulators of insulin action, and as transcription factor ligands.

描述（由申请人提供）：膳食摄入过量的脂肪或碳水化合物会导致三酰甘油（TAG）的合成和储存增加。有助于TAG合成的长链脂肪酸（FA）必须首先通过长链转化为酰基辅酶A。因为酰基辅酶A 合成酶 (ACSL) 位于储存和线粒体的分支点 ¿ -氧化，所形成的酰基辅酶A的命运可能会导致或抵消营养失调与肥胖、脂肪肝、动脉粥样硬化和糖尿病等 TAG 储存增加有关。我们研究发现 1) ACSL1 能够将 FA 引导至 ¿ -高氧化组织中的氧化，因为该酶与肉毒碱酰基转移酶相互作用以传递其酰基辅酶A产物；2) ACSL1的功能在肝脏中不同，因为至少50%的蛋白质存在于与肉毒碱相互作用的内质网上；甘油脂酰基转移酶；3) 这些差异的机制在于 ACSL1 的膜关联和磷酸化状态。此外，我们认为组织使用葡萄糖而不是 FA 作为燃料来源并非没有成本，并且这种使用产生的代谢和功能问题可能对器官功能和胰岛素信号传导产生危险。假设每个 ACSL 将 FA 导向特定的命运，ACSL4 同种型的功能是调节花生四烯酸进入磷脂合成途径和类二十烷酸形成途径，我们的研究将解决我们关于 FA 代谢命运的知识中的关键差距。复杂脂质形成的底物，作为代谢燃料、作为类二十烷酸信号传导的前体、作为胰岛素作用的调节剂以及作为转录因子配体。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Acyl-CoA metabolism and partitioning.

DOI：
10.1146/annurev-nutr-071813-105541
发表时间：
2014
期刊：
Annual review of nutrition
影响因子：
8.9
作者：
Grevengoed TJ;Klett EL;Coleman RA
通讯作者：
Coleman RA

Propylisopropylacetic acid (PIA), a constitutional isomer of valproic acid, uncompetitively inhibits arachidonic acid acylation by rat acyl-CoA synthetase 4: a potential drug for bipolar disorder.

DOI：
10.1016/j.bbalip.2013.01.008
发表时间：
2013-04
期刊：
Biochimica et biophysica acta
影响因子：
0
作者：
Modi HR;Basselin M;Taha AY;Li LO;Coleman RA;Bialer M;Rapoport SI
通讯作者：
Rapoport SI

Diminished acyl-CoA synthetase isoform 4 activity in INS 832/13 cells reduces cellular epoxyeicosatrienoic acid levels and results in impaired glucose-stimulated insulin secretion.

DOI：
10.1074/jbc.m113.481077
发表时间：
2013-07-26
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Klett, Eric L;Chen, Shufen;Coleman, Rosalind A
通讯作者：
Coleman, Rosalind A

mTORtuous effect on the elastic heart.

DOI：
10.18632/oncotarget.4788
发表时间：
2015-07-10
期刊：
Oncotarget
影响因子：
0
作者：
Schisler JC;Coleman RA
通讯作者：
Coleman RA

Valproate uncompetitively inhibits arachidonic acid acylation by rat acyl-CoA synthetase 4: relevance to valproate's efficacy against bipolar disorder.

丙戊酸非竞争性抑制大鼠酰基辅酶 A 合成酶 4 的花生四烯酸酰化：与丙戊酸对抗双相情感障碍的功效相关。

DOI：
10.1016/j.bbalip.2010.12.006
发表时间：
2011
期刊：
Biochimica et biophysica acta
影响因子：
0
作者：
Shimshoni,JakobA;Basselin,Mireille;Li,LeiO;Coleman,RosalindA;Rapoport,StanleyI;Modi,HirenR
通讯作者：
Modi,HirenR