Regulation of Coenzyme A Levels by Pantothenate Kinase

泛酸激酶对辅酶 A 水平的调节

• 批准号: 6640115
• 负责人: SUZANNE JACKOWSKI
• 金额: $ 25.5万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6640115
• 关键词: N acylaminoacid; coenzyme A; enzyme activity; enzyme biosynthesis; gene expression; genetically modified animals; isozymes; laboratory mouse; metabolism; protein kinase; transcription factor; vitamin B complex

DESCRIPTION (provided by applicant): The long-term goal is to define the mechanisms that control the intracellular concentration of CoA and understand the physiological significance of this regulatory system. CoA is an essential acyl group carrier, and is produced by a universal series of reactions starting from the vitamin pantothenate (Pan). Pan is an abundant vitamin and under normal physiological circumstances is present in significant excess over the amounts needed to support CoA biosynthesis. Fine control over CoA levels is important to support physiological adjustments in intermediary metabolism not only because CoA and its thioesters are key cofactors in energy generating pathways, but they also allosterically control carbon flux at key metabolic control points. It is clear that the cellular activity of Pan kinase (PanK) regulates CoA biosynthesis and there are two mechanisms that govern this parameter. First, feedback inhibition of PanK by CoA and its thioesters establishes the upper limit for the cellular CoA concentration at a specific level of PanK expression. Second, the steady state CoA level is adjusted by altering PanK gene expression. The intracellular CoA levels fluctuate in response to hormones, diet, and drugs, and are also dysregulated in metabolic disorders. There are multiple PanK genes that exhibit tissue specific expression, and the importance of specific isozyme expression is underscored by the finding that mutations in the human PANK2 gene are responsible for a hereditary neuropathy. We hypothesize that changes in CoA levels are a prerequisite for altering the balance between fatty acid utilization and storage, and that elevation of PanK isozyme expression is necessary for functional peroxisome proliferation and fatty acid oxidation. CoA biosynthesis has been a neglected research area, but our recent identification and preliminary characterization of the PanK genes, cDNAs and proteins open the door to the molecular dissection of the importance of these gene products to the control of mammalian intermediary metabolism. The Research Plan is organized around two aims: 1) To characterize the PanK isozymes and define the biochemical mechanisms that regulate their activity; and 2) To define the mechanisms that lead to altered PanK gene expression and the metabolic importance of controlling CoA levels. This research will contribute to the understanding of global metabolic control and human disease by defining the importance of CoA regulation by specific PanK isozymes.

描述（由申请人提供）：长期目标是确定控制 CoA 细胞内浓度的机制并了解该调节系统的生理意义。 CoA 是一种重要的酰基载体，由维生素泛酸 (Pan) 起始的一系列通用反应产生。潘是一种丰富的维生素，在正常生理情况下，其含量远远超过支持 CoA 生物合成所需的量。对 CoA 水平的精细控制对于支持中间代谢的生理调节非常重要，不仅因为 CoA 及其硫酯是能量生成途径中的关键辅助因子，而且它们还在关键代谢控制点变构控制碳通量。很明显，Pan 激酶 (PanK) 的细胞活性调节 CoA 生物合成，并且有两种机制控制该参数。首先，CoA 及其硫酯对 PanK 的反馈抑制确定了特定 PanK 表达水平下细胞 CoA 浓度的上限。其次，通过改变 PanK 基因表达来调节稳态 CoA 水平。细胞内 CoA 水平会因激素、饮食和药物而发生波动，并且在代谢紊乱时也会失调。有多种 PanK 基因表现出组织特异性表达，人类 PANK2 基因突变导致遗传性神经病的发现强调了特异性同工酶表达的重要性。我们假设 CoA 水平的变化是改变脂肪酸利用和储存之间平衡的先决条件，并且 PanK 同工酶表达的升高对于功能性过氧化物酶体增殖和脂肪酸氧化是必要的。 CoA 生物合成一直是一个被忽视的研究领域，但我们最近对 PanK 基因、cDNA 和蛋白质的鉴定和初步表征为分子解析这些基因产物对哺乳动物中间代谢控制的重要性打开了大门。该研究计划围绕两个目标进行组织：1) 表征 PanK 同工酶并定义调节其活性的生化机制； 2) 明确导致 PanK 基因表达改变的机制以及控制 CoA 水平的代谢重要性。这项研究将通过明确特定 PanK 同工酶调节 CoA 的重要性，有助于理解全球代谢控制和人类疾病。