Studies on the impact of acetyl-cysteine on metabolism

乙酰半胱氨酸对代谢影响的研究

• 批准号: 10574934
• 负责人: Matthew D Hirschey
• 金额: $ 23.51万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10574934
• 关键词: Ablation; Acceleration; Acetyl Coenzyme A; Acetylation; Acetylcysteine; Acetyltransferase; Acyl Coenzyme A; Adipose tissue; Affect; Age; Aging; Amides; Applications Grants; Automobile Driving; Biochemical; Biological; Biological Assay; Biological Process; Biology; Blood; Brain; Brown Fat; Cell physiology; Cells; Chemicals; Chemistry; Chromatin; Cysteine; Data; Detection; Development; Disease; Dithiothreitol; Drug or chemical Tissue Distribution; Elements; Excision; Fasting; Gender; Gene Expression; Generations; Glutathione Reductase; Goals; Harvest; Health; Heart; Histones; Homeostasis; In Vitro; Knowledge; Liver; Lysine; Mass Spectrum Analysis; Measures; Mediator; Metabolic; Metabolic Control; Metabolism; Methods; Mitochondria; Modeling; Modification; Mus; Nutrient; Oxidation-Reduction; Peptides; Pharmaceutical Preparations; Phenotype; Physiological; Play; Post-Translational Protein Processing; Posttranslational Amino Acid Modification; Preparation; Prevalence; Process; Proline Dehydrogenase; Protein Acetylation; Proteins; Proteome; Proteomics; Public Health; Reaction; Regulation; Role; Running; Sampling; Series; Side; Signal Transduction; Site; Skeletal Muscle; Skin; Source; Surveys; Tissues; Wild Type Mouse; Work; detection of nutrient; experimental study; feeding; innovation; novel; nutrient metabolism; preservation; prevent; protein function; response; sensor; therapeutically effective; thioester; treatment strategy; tris(2-carboxyethyl)phosphine

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.

细胞将营养感知和新陈代谢结合在一起，以协调细胞对特定营养的适当反应 消息来源。其中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 研究修饰和调节从染色质和基因表达到 新陈代谢。我们在本申请中提供的初步数据对乙酰化前景进行了扩展 描述一种名为乙酰半胱氨酸的新蛋白质修饰。这种修饰在蛋白质组中大量存在 富含与新陈代谢有关的蛋白质。这些早期数据揭示了我们对 乙酰化前景：这种新修饰的组织分布是什么？在哪一种生理状态下 这种修改的条件会发生变化吗？哪些蛋白质被修饰？其细胞后果是什么？ 半胱氨酸过度乙酰化？这与衰老有关吗？迫切需要全面了解 蛋白质修饰，以便更好地了解生理营养感知以及它是如何在 疾病的背景。尽管人们普遍认为赖氨酸修饰可以参与细胞内营养 由于乙酰半胱氨酸是敏感的，并随着年龄的增长而失调，因此没有关于乙酰半胱氨酸的数据。因此，这一行动的唯一目标是 探索性拨款的应用是确定半胱氨酸的位置(S)、后果和生理介质 乙酰化。目的1根据组织类型和代谢状态调查半胱氨酸乙酰化的发生率。在一个 互补平行方法，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，因为它揭示了一个以前被忽视的蛋白质修饰。此外，在给定的 半胱氨酸在氧化还原动态平衡中的核心作用，它有望在代谢动态平衡中发挥核心作用。我们把 四是概念和技术创新，既遵循定向假说，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 细胞内信号和代谢动态平衡的新方面可能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。