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Coenzyme A Regulation of Metabolism

辅酶 A 代谢调节

基本信息

批准号：
8663281
负责人：
SUZANNE JACKOWSKI
金额：
$ 39.38万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
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：
2002-07-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8663281
关键词：
A Mouse Acetates Acetyl Coenzyme A Adipose tissue Adverse effects Affect Anabolism Animals Attention Backcrossings Biochemical Pathway Biochemistry Biology Buffers Carnitine Cells Chemicals Coenzyme A Dependence Dependovirus Development Diabetic mouse Diet Euglycemic Clamping Evaluation Exercise Failure Fasting Fatty Acids Feedback GLUT4 gene Generations Genes Genetic Polymorphism Gluconeogenesis Glucose Glucose Clamp Grant Hepatic Homeostasis Human Hydrolase Hyperglycemia Hyperinsulinism Individual Insulin Insulin Receptor Insulin Resistance Ketones Knockout Mice Lead Lipids Liver Measures Medical Messenger RNA Metabolic Metabolic syndrome Metabolism Morbidity - disease rate Mus Muscle Non-Insulin-Dependent Diabetes Mellitus Nutritional Obesity Organ Outcomes Research Pantothenate kinase Pathway interactions Performance Phenotype Population Property Protein Isoforms Protein Kinase Receptor Signaling Refractory Regulation Research Role Series Serum Site Skeletal Muscle Syndrome System Testing Therapeutic Tissues Transcript Triglycerides United States Work base blood glucose regulation db/db mouse diabetic feeding genome wide association study glucose production glucose tolerance glucose uptake hepatic gluconeogenesis improved inhibitor/antagonist insight insulin sensitivity kinase inhibitor lipid disorder moderate obesity mouse model muscle metabolism programs research study small molecule thioester tool

项目摘要

DESCRIPTION (provided by applicant): This proposal is an extension of an evolving program investigating the importance of pantothenate kinase (PanK) regulation of coenzyme A (CoA) biosynthesis to the control of intermediary metabolism. The accomplished aims of the last grant period defined the regulatory properties and tissue-specific distribution of the PanK isoforms, generated a knockout mouse model that was used to reveal the critical importance of increasing CoA levels in fasting metabolism, employed a chemical biology approach to identify small molecule PanK inhibitors, and identified acyl-carnitine as a PanK activator. These results have refined our overall idea that altering the intracellular CoA concentration is essential for reprogramming metabolism. In the past, intracellular CoA has been considered to be in excess of what is needed to fully support CoA-dependent biochemistry, with acetyl-CoA exerting feedback control over PanK activity to buffer the cellular CoA content. This view is not correct. Our results show that the CoA supply is dynamically regulated and the failure to modulate CoA content directly impacts fuel utilization by the metabolic network. This unappreciated aspect of regulation is central to understanding the nutritional reprogramming of intermediary metabolism. The experiments in Aim #1 will determine the role of adjusting CoA levels in the transition of muscle from fed to fasting metabolism. The results from this part of the study will be of central importance to understanding the dependence of energy generation in muscle on CoA content. In humans, there is an association between low serum insulin levels and polymorphisms in the PANK1 gene. Prominent phenotypes of our Pank1/ knockout mouse are lower serum glucose, triglycerides and insulin levels. In Aim #2, we will use our Pank1/ mouse model to define the underlying metabolic basis for reduced insulin levels and to determine if muscle is the primary site for increased glucose tolerance in these animals. CoA and its thioesters are concentration- dependent substrates and allosteric regulators of key control points in intermediary metabolism, suggesting that the pharmacological manipulation of CoA levels via PanK inhibition could reprogram metabolism. This idea was validated by our experiments with a PanK inhibitor that lowers hepatic CoA and serum glucose in mice. In Aim #3, we will use this inhibitor to reduce total CoA content to pharmacologically reprogram hepatic metabolism to suppress gluconeogenesis in diet-induced obesity, and determine if the elevation of hepatic CoA is sufficient to increase glucose production. This original approach to reprogramming intermediary metabolism will define the role of CoA in hepatic gluconeogenesis and provide insight into the factors that give rise to human disorders of lipid and glucose homeostasis.

描述(由申请人提供)：这项建议是一个不断发展的计划的扩展，该计划调查了辅酶A(CoA)生物合成的泛酸激酶(Pank)调节对中间代谢控制的重要性。上一次资助期间完成的目标确定了Pank异构体的调节特性和组织特异性分布，产生了用于揭示提高CoA水平在禁食代谢中的关键重要性的基因敲除小鼠模型，采用化学生物学方法鉴定小分子Pank抑制剂，并将酰肉碱确定为Pank激活剂。这些结果提炼了我们的总体想法，即改变细胞内CoA浓度对于重新编程代谢是必不可少的。在过去，细胞内的CoA被认为超过了完全支持CoA依赖的生化所需的水平，乙酰CoA对Pank活性进行反馈控制，以缓冲细胞CoA的含量。这种观点是不正确的。我们的结果表明，CoA的供应是动态调节的，未能调节CoA含量直接影响代谢网络对燃料的利用。调节的这一未被认识的方面是理解中间代谢的营养重新编程的中心。目标1中的实验将确定调节辅酶A水平在肌肉从摄食到禁食代谢转变过程中的作用。这部分研究的结果对于理解肌肉中能量产生对辅酶A含量的依赖至关重要。在人类中，低血清胰岛素水平与PANK1基因的多态有关。我们的Pank1/基因敲除小鼠的突出表型是较低的血糖、甘油三酯和胰岛素水平。在目标2中，我们将使用我们的Pank1/小鼠模型来确定胰岛素水平降低的潜在代谢基础，并确定肌肉是否是这些动物葡萄糖耐量增加的主要部位。CoA及其硫代酯是中间代谢关键控制点的浓度依赖底物和变构调节剂，提示通过Pank抑制对CoA水平进行药理调控可以重新编程代谢。我们用Pank抑制剂进行的实验验证了这一想法，该抑制剂可以降低小鼠的肝脏CoA和血糖。在目标3中，我们将使用这种抑制剂来降低总CoA含量，从药理上重新编程肝脏代谢，以抑制饮食诱导的肥胖中的糖异生，并确定肝脏CoA的升高是否足以增加葡萄糖的产生。这种重新编程中间代谢的原创性方法将定义CoA在肝脏糖异生中的作用，并提供对导致人类脂质和葡萄糖动态平衡紊乱的因素的洞察。

项目成果

期刊论文数量（30）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Physiological roles of the pantothenate kinases.

泛酸激酶的生理作用。

DOI：
10.1042/bst20140096
发表时间：
2014-08
期刊：
Biochemical Society transactions
影响因子：
3.9
作者：
Dansie LE;Reeves S;Miller K;Zano SP;Frank M;Pate C;Wang J;Jackowski S
通讯作者：
Jackowski S

Acyl carrier protein is a cellular target for the antibacterial action of the pantothenamide class of pantothenate antimetabolites.

酰基载体蛋白是泛酰胺类泛酸抗代谢物抗菌作用的细胞靶标。

DOI：
10.1074/jbc.m409607200
发表时间：
2004
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Zhang,Yong-Mei;Frank,MatthewW;Virga,KristopherG;Lee,RichardE;Rock,CharlesO;Jackowski,Suzanne
通讯作者：
Jackowski,Suzanne

Pantothenate kinase 1 is required to support the metabolic transition from the fed to the fasted state.