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

了解导致糖尿病代谢紊乱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，大量的证据支持线粒体超负荷理论，包括对支链氨基酸(BCAA)代谢异常的特殊作用。我们的目标是确定来自支链氨基酸代谢的酰基辅酶A物种如何诱导蛋白质和组蛋白的修饰，并评估在营养过剩的情况下，蛋白质超酰化如何影响代谢调节。我们最近发现了一类来自亮氨酸氧化的高活性酰基辅酶A物种，它们可以修饰参与支链氨基酸分解代谢的酶。我们还发现了线粒体sirtuin SIRT4的一种新的酶活性来消除这些修饰，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新陈代谢和营养动态平衡的意外控制水平。在这个项目中，我们将在这些发现的基础上，专注于以下具体目标：1)确定营养通量的变化如何导致线粒体蛋白质酰化的变化；2)确定在营养过剩的背景下线粒体蛋白质超酰化对BCAA酶功能的影响；以及3)确定来自营养代谢的代谢物是如何被感知并整合到表观基因组中的。总而言之，这些研究结合了一个全面的实验设计和一个创新的概念框架，以确定来自中央碳代谢的中间代谢物如何驱动特定的营养感知反应。此外，这项研究将建立一个知识基础，以进一步了解这些途径如何有助于糖尿病的病理生理学。最终，这些研究将加深我们对新出现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。

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.