Regulation of Coenzyme A Levels by Panothenate Kinase

泛酸激酶对辅酶 A 水平的调节

• 批准号: 7256677
• 负责人: SUZANNE JACKOWSKI
• 金额: $ 29.66万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7256677
• 关键词: Acetyl Coenzyme A; Address; Affinity; Anabolism; Area; Binding; Biochemical; Biology; Carbon; Carnitine; Cells; Coenzyme A; Complex; Coupled; Data; Development; Diabetes Mellitus; Diet; Disease; Energy Metabolism; Enzymes; Exhibits; Exons; Fatty Acids; Feedback; Foundations; Future; Generations; Genes; Glucose; Grant; Hormones; Human; In Vitro; Isoenzymes; Knock-out; Laboratories; Ligands; Localized; Mammals; Mediating; Metabolic; Metabolic Diseases; Metabolism; Missense Mutation; Mitochondria; Molecular; Mutation; Neurologic; Numbers; Palmitoyl Coenzyme A; Pantothenate kinase; Pantothenate kinase-associated neurodegeneration; Pathway interactions; Pattern; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Physiological; Process; Progress Reports; Property; Protein Biochemistry; Protein Isoforms; Proteins; Rate; Reaction; Refractory; Regulation; Research; Research Personnel; Role; Series; Signal Transduction; Source; System; Vitamins; Work; acyl group; base; cofactor; disease-causing mutation; human disease; lipid metabolism; mouse model; nervous system disorder; novel; oxidation; pantothenate; programs; response; thioester

DESCRIPTION (provided by applicant): Coenzyme A (CoA) is the major acyl group carrier in biology and an essential cofactor in intermediary metabolism. Free CoA (unacylated) and its thioesters are allosteric ligands that govern the carbon flux through key metabolic enzymes and, in turn, control energy generation. There is ample evidence that intracellular CoA levels fluctuate in response to hormones, diet, and drugs, and are dysregulated in metabolic disorders such as diabetes. CoA is produced by a universal series of reactions starting from the vitamin pantothenate, and the flux through this pathway is controlled by the first enzyme, pantothenate kinase (PanK). Mammals have multiple PanK enzymes, each with unique regulatory properties, expression patterns and intracellular distributions. The critical importance of PanK in metabolism has been extensively validated in prokaryotic systems but there are significant gaps in our understanding of the biochemical regulation and role of the multiple mammalian PanK enzymes in the physiological control of metabolism. The importance of these enzymes was brought into sharp focus in mammalian systems by the discovery of the association of mutations in the human PANK2 gene with a progressive neurological disorder called PKAN. The human PanK2 isozyme is associated with mitochondria. The initial idea was that all disease- causing mutations inactivated PanK2 enzymatic function; however, our comprehensive analysis illustrates that a significant percentage of the mutations do not inactivate PanK2 suggesting that these missense mutations alter an important regulatory feature of the protein. We propose that mitochondrial PanK has a unique regulatory role in the metabolic adaptation of CoA levels to the utilization of fatty acids as a fuel source. Specifically, CoA levels must increase for mitochondria to efficiently carry out fatty acid p-oxidation, and PanK2 senses the status of mitochondrial p-oxidation and adjusts the rate of CoA biosynthesis accordingly. The results from the last grant period reveal the novel regulatory biochemical mechanism for PanK2 activity and we will investigate the mechanistic basis for the complex control of PanK2 activity and determine if the disease-causing PanK2 mutations are altered in this property. We will also address the role of PanK2 in regulating the cellular response to metabolic shift from glucose to fatty acids in cells. These results will provide essential information about the control systems that regulate energy metabolism in mammals and establish the scientific foundation for future development of hypotheses regarding the metabolic basis for the human PKAN disease. The research requires expertise in the areas of CoA biosynthesis, lipid metabolism and protein biochemistry which are the clear strengths of the investigative team assembled to pursue this problem.

性状（申请人提供）：辅酶A（CoA）是生物学中主要的酰基载体，也是中间代谢的必需辅因子。游离CoA（未酰化）及其硫酯是变构配体，通过关键代谢酶控制碳通量，进而控制能量产生。有充分的证据表明，细胞内辅酶A水平波动响应激素，饮食和药物，并在代谢紊乱如糖尿病失调。辅酶A是由维生素泛酸开始的一系列通用反应产生的，并且通过该途径的流量由第一种酶泛酸激酶（PanK）控制。哺乳动物具有多种PanK酶，每种酶都具有独特的调节特性、表达模式和细胞内分布。PanK在代谢中的重要性已经在原核系统中得到了广泛的验证，但是我们对多种哺乳动物PanK酶在代谢的生理控制中的生化调节和作用的理解存在显着的差距。通过发现人类PANK 2基因突变与称为PKAN的进行性神经系统疾病的关联，这些酶的重要性在哺乳动物系统中引起了强烈关注。人类PanK 2同工酶与线粒体相关。最初的想法是所有致病突变都使PanK 2酶功能失活;然而，我们的综合分析表明，相当大比例的突变不会使PanK 2失活，这表明这些错义突变改变了蛋白质的重要调控特征。我们认为，线粒体PanK在辅酶A水平代谢适应脂肪酸作为燃料来源的利用中具有独特的调节作用。具体来说，辅酶A水平必须增加线粒体才能有效地进行脂肪酸β-氧化，PanK 2可以感知线粒体β-氧化的状态，并相应地调节辅酶A生物合成的速率。最后一个资助期的结果揭示了PanK 2活性的新的调节生化机制，我们将研究PanK 2活性复杂控制的机制基础，并确定致病PanK 2突变是否在此属性中发生改变。我们还将讨论PanK 2在调节细胞中从葡萄糖到脂肪酸的代谢转变的细胞反应中的作用。这些结果将提供有关调节哺乳动物能量代谢的控制系统的重要信息，并为未来发展人类PKAN疾病代谢基础的假说奠定科学基础。该研究需要CoA生物合成，脂质代谢和蛋白质生物化学领域的专业知识，这些领域是为解决这一问题而组建的调查小组的明显优势。