Post-Translational and Epigenetic Control of Branched-Chain Amino Acid Metabolism

支链氨基酸代谢的翻译后和表观遗传控制

基本信息

批准号：
10225807
负责人：
Matthew D Hirschey
金额：
$ 12.26万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10225807
关键词：
Acetyl Coenzyme A Acetylation Acyl Coenzyme A Acylation Address Adult Affect Biological Branched-Chain Amino Acids Carbon Catabolism Complex Complications of Diabetes Mellitus Coupling Data Defect Development Diabetes Mellitus Diet Disease Enzymes Epigenetic Process Event Excision Experimental Designs Family Foundations Functional disorder Gene Expression Genetic Transcription Glucose Goals Health Hepatic Histone Acetylation Histones Homeostasis Human Insulin Resistance Intervention Isotope Labeling Knowledge Laboratories Lead Leucine Lipids Lysine Macronutrients Nutrition Maps Measurement Measures Metabolic Metabolic Control Metabolic Pathway Metabolism Methods Mission Mitochondria Mitochondrial Proteins Modeling Modification Molecular Mus Names Non-Insulin-Dependent Diabetes Mellitus Nutrient Obesity Overnutrition Pathway interactions Peptides Pharmacology Physiological Plasma Play Post-Translational Protein Processing Prevention Protein Acetylation Proteins Proteome Proteomics Public Health Publishing Reader Reagent Regulation Research Role SIRT1 gene Shapes Sirtuins Site-Directed Mutagenesis Sum Technology Tissues United States National Institutes of Health acyl group amino acid metabolism deacylation detection of nutrient epigenome genetic manipulation histone modification innovation metabolomics non-histone protein novel novel therapeutics nutrient metabolism oxidation prevent response theories

项目摘要

Understanding the molecular mechanisms that contribute to dysregulated metabolism in diabetes is essential for developing effective prevention methods and discovering a cure. Over the past 10 years, substantial evidence supports the mitochondrial overload theory of overnutrition-induced metabolic dysregulation, including a specific role for dysregulated branched-chain amino acid (BCAA) metabolism. The goal here is to identify how acyl-CoA species derived from BCAA metabolism induce protein and histone modifications, and to assess how protein hyperacylation affects metabolic regulation in the setting of overnutrition. We recently discovered a class of highly reactive acyl-CoA species derived from leucine oxidation that modify enzymes involved in BCAA catabolism. We also uncovered a novel enzymatic activity of the mitochondrial sirtuin SIRT4 to remove these modifications, thereby regulating leucine catabolic flux. These discoveries define a new paradigm of protein acylation and deacylation, and identify an unexpected level of control over BCAA metabolism and nutrient homeostasis. In this project, we will build upon these findings and focus on the following Specific Aims: 1) To determine how alterations in nutrient flux lead to changes in mitochondrial protein acylation; 2) To determine the consequence of mitochondrial protein hyperacylation on BCAA enzyme function in the setting of over-nutrition; and 3) To determine how metabolites derived from nutrient metabolism are sensed and integrated into the epigenome. Together, these studies combine a comprehensive experimental design and an innovative conceptual framework in order to determine how intermediary metabolites derived from central carbon metabolism drive specific nutrient-sensing responses. Furthermore, this study will build a foundation of knowledge to further how these pathways contribute to the pathophysiology of diabetes. Ultimately, these studies will deepen our understanding of emergent, novel metabolic control mechanisms, and have the potential to inform the development of new therapies and prevention methods.

了解导致糖尿病代谢失调的分子机制对于开发有效的预防方法和发现治疗方法至关重要。在过去的 10 年里，大量证据支持营养过剩引起的代谢失调的线粒体超载理论，包括支链氨基酸 (BCAA) 代谢失调的特定作用。这里的目标是确定源自 BCAA 代谢的酰基辅酶 A 物种如何诱导蛋白质和组蛋白修饰，并评估蛋白质过度酰化如何影响营养过剩情况下的代谢调节。我们最近发现了一类源自亮氨酸氧化的高反应性酰基辅酶A，可以修饰支链氨基酸分解代谢中涉及的酶。我们还发现了线粒体 Sirtuin SIRT4 的一种新酶活性，可以消除这些修饰，从而调节亮氨酸分解代谢通量。这些发现定义了蛋白质酰化和脱酰化的新范式，并确定了对支链氨基酸代谢和营养稳态的意想不到的控制水平。在这个项目中，我们将在这些发现的基础上，重点关注以下具体目标：1）确定营养通量的变化如何导致线粒体蛋白酰化的变化； 2) 确定营养过剩情况下线粒体蛋白过度酰化对支链氨基酸酶功能的影响； 3) 确定如何感知来自营养代谢的代谢物并将其整合到表观基因组中。这些研究结合了全面的实验设计和创新的概念框架，以确定来自中心碳代谢的中间代谢物如何驱动特定的营养感应反应。此外，这项研究将为进一步了解这些途径如何促进糖尿病的病理生理学奠定知识基础。最终，这些研究将加深我们对新兴的、新颖的代谢控制机制的理解，并有可能为新疗法和预防方法的开发提供信息。