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：
10164761
负责人：
Matthew D Hirschey
金额：
$ 40.25万
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/10164761
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 dietary 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.

了解糖尿病中代谢失调的分子机制对于开发有效的预防方法并发现治愈方法至关重要。在过去的10年中，大量证据支持了牙齿营养诱导的代谢失调的线粒体过载理论，包括对失调的分支链氨基酸（BCAA）代谢的特定作用。这里的目的是确定从BCAA代谢衍生的酰基-COA物种如何诱导蛋白质和组蛋白修饰，并评估蛋白质超囊酸如何在营养不良的情况下影响代谢调节。最近，我们发现了一类高反应性酰基辅酶A种，这些酰基氧化源自亮氨酸氧化，这些物种改变了参与BCAA分解代谢的酶。我们还发现了线粒体Sirtuin Sirt4的新型酶促活性，以去除这些修饰，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BCAA代谢和营养稳态的意外控制水平。在这个项目中，我们将基于这些发现并关注以下特定目的：1）确定营养通量的变化如何导致线粒体蛋白酰基化的变化； 2）确定线粒体蛋白超筛化对BCAA酶功能的结果； 3）为了确定如何感知从营养代谢的代谢产物，并整合到表观基因组中。这些研究共同结合了一个全面的实验设计和创新的概念框架，以确定中间代谢产物如何源自中央碳代谢驱动特定的营养感应反应。此外，这项研究将建立知识的基础，以进一步促进这些途径如何促进糖尿病的病理生理学。最终，这些研究将加深我们对新兴的新型代谢控制机制的理解，并有可能告知新疗法和预防方法的发展。