Studies on the impact of acetyl-cysteine on metabolism

细胞整合营养感应和代谢，以协调对特定营养的适当细胞反应 源头发生这种情况的一种方式是通过蛋白质的翻译后修饰。乙酰赖氨酸是最重要的 研究修饰和调节动态过程，从染色质和基因表达， 新陈代谢.我们在本申请中提供的初步数据扩展了乙酰化景观， 描述了一种叫做乙酰半胱氨酸的新蛋白质修饰。这种修饰在整个蛋白质组中是丰富的 并且富含参与代谢的蛋白质。这些早期的数据揭示了我们在理解 乙酰化景观：这种新修饰的组织分布是什么？在这种生理条件下， 这一修改是否会改变？哪些蛋白质被修饰？细胞的结果是什么 半胱氨酸过度乙酰化？这与衰老有关吗？有一个关键需要了解的全面 蛋白质修饰，以便更好地了解生理营养感测以及它如何在 疾病的设置。尽管赖氨酸修饰可以参与细胞内营养的调节， 感测并且随着老化失调，没有关于乙酰半胱氨酸的数据。因此，这一单一目标 探索性拨款申请是为了确定半胱氨酸的位点、后果和生理介质 乙酰化目的1将通过组织类型和代谢状态调查半胱氨酸乙酰化的发生率。中 作为互补的平行方法，目标2将表征半胱氨酸乙酰化对蛋白质活性的影响。 这个项目意义重大，因为它揭示了以前被忽视的蛋白质修饰。再加上 尽管半胱氨酸在氧化还原体内平衡中的中心作用，但它准备在代谢体内平衡中发挥中心作用。我们把 提出概念和技术创新，既遵循有指导的假设，又允许无偏见的发现 这种新的蛋白质修饰的最重要的方面。该项目的成功完成将揭示一个 细胞内信号和代谢稳态的新方面，可能会影响我们对氧化还原的理解 衰老过程中的生物学和新陈代谢。

Cells integrate nutrient sensing and metabolism to coordinate proper cellular responses to a particular nutrient source. One way this occurs is via post-translational modifications of proteins. Acetyl-lysine is among the most studied modification and regulates dynamic processes ranging from chromatin and gene expression to metabolism. Our preliminary data presented in this application expand upon the acetylation landscape and describe a new protein modification called acetyl-cysteine. This modification is abundant across the proteome and is enriched on proteins involved in metabolism. These early data reveal key gaps in our understanding of the acetylation landscape: what is the tissue distribution of this new modification? Under which physiological conditions does this modification change? Which proteins are modified? What is the cellular consequence of cysteine hyperacetylation? Is this relevant for aging? There is a critical need to understand the full range of protein modifications in order to better understand physiological nutrient sensing and how it is perturbed in the setting of disease. Although it is widely accepted that lysine modifications can participate in intracellular nutrient sensing and is dysregulated with aging, no data exists on acetyl-cysteine. Therefore, the single objective of this exploratory grant application is to determine the site(s), consequences, and physiologic mediators of cysteine acetylation. Aim 1 will investigate the prevalence of cysteine acetylation by tissue type and metabolic state. In a complementary parallel approach, Aim 2 will characterize the effects of cysteine acetylation on protein activity. This project is significant because it uncovers a previously overlooked protein modification. Furthermore, given cysteine’s central role in redox homeostasis, it is poised to play a central role in metabolic homeostasis. We put forth conceptual and technical innovations that will both follow directed hypotheses and allow unbiased discovery of the most important aspects of this new protein modification. Successful completion of this project will reveal a new aspect of intracellular signaling and metabolic homeostasis that could influence our understanding of redox biology and metabolism during aging.