Chemical/biochemical tools for studying novel protein acyl lysine modifications

用于研究新型蛋白质酰基赖氨酸修饰的化学/生化工具

• 批准号: 8372450
• 负责人: Hening Lin
• 金额: $ 57.57万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-17 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8372450
• 关键词: Acetyl Coenzyme A; Acetylation; Acetyltransferase; Acylation; Address; Affinity; Antibodies; Apoptosis; Biochemical; Biological; Biological Process; Biology; Cells; Chemicals; Chemistry; Deacetylase; Development; Drug Delivery Systems; Enzymes; Epigenetic Process; Gene Expression; Goals; Histones; Individual; Knock-out; Laboratories; Lysine; Malignant Neoplasms; Mammalian Cell; Mammals; Metabolic; Metabolism; Methods; Modification; Pathway interactions; Peptides; Play; Post-Translational Protein Processing; Process; Protein Acetylation; Proteins; Reagent; Regulation; Relative (related person); Research; Role; Sirtuins; Site; Testing; Transcriptional Regulation; Transferase; Vorinostat; Warburg Effect; Western Blotting; acyl group; analog; biological systems; fatty acylation; human disease; inhibitor/antagonist; insight; interest; novel; novel therapeutics; protein function; protein metabolism; therapeutic target; tool

DESCRIPTION (provided by applicant): Protein posttranslational modifications are important for regulating protein function and are involved in numerous biological processes. Protein acetylation, controlled by acetyltransferases and deacetylases, are known to play important roles in regulation of transcription and metabolism. The acetyl donor, acetyl-CoA, is a metabolic intermediate in cells. Recently, our laboratory discovered several novel acyl lysine modifications that are structurally very different from acetyl. We have shown that these new acyl lysine modifications occur in mammalian cells and there are dedicated enzymes (sirtuins) that can remove them efficiently. These new acyl lysine modifications, like acetylation, also come from common metabolic intermediates, suggesting that these modifications may be a mechanism of sensing metabolism to regulate protein function. Studying these new modifications will allow us to better understand the chemistry of biological systems. The study has the potential to provide answers to a number of puzzles in the protein acetylation field, such as the lack of enzymatic activity for about half of the protein deacetylases. Because these acyl lysine modifications have not been studied before, no tools are available to investigate them. The existence of multiple acyl lysine modifications also adds a layer of technical complexity to the study of these modifications. The goal of this proposal is to develop new and better methods to detect and quantify these modifications and then use these methods to investigate the occurrence, regulation, and function of these modifications. PUBLIC HEALTH RELEVANCE: This proposal aims to develop chemical and biochemical tools to study novel protein acyl lysine modifications. These acyl lysine modifications are recently discovered in our laboratory and are structurally different from lysine acetylation, which is known to control numerous biological pathways and considered important drug target. The proposed study will provide fundamental understandings of the chemistry of metabolism and protein regulation that will eventually facilitate the development of new therapeutics to treat human diseases.

描述（由申请人提供）：翻译后修饰对于调节蛋白质功能很重要，并且参与了许多生物学过程。众所周知，由乙酰转移酶和脱乙酰基酶控制的蛋白乙酰化在转录和代谢的调节中起着重要作用。乙酰供体乙酰辅酶A是细胞中的代谢中间体。最近，我们的实验室发现了几种与乙酰基在结构上非常不同的新型酰基赖氨酸修饰。我们已经表明，这些新的酰基赖氨酸修饰发生在哺乳动物细胞中，并且有专门的酶（Sirtuins）可以有效去除它们。这些新的酰基赖氨酸修饰（如乙酰化）也来自常见的代谢中间体，这表明这些修饰可能是传感代谢来调节蛋白质功能的机制。研究这些新的修饰将使我们能够更好地了解生物系统的化学反应。这项研究有可能为蛋白质乙酰化场中多个难题提供答案，例如大约一半蛋白脱乙酰基酶缺乏酶促活性。由于这些酰基赖氨酸的修饰以前尚未研究过，因此没有任何可用的工具来调查它们。多种酰基赖氨酸修饰的存在也为这些修饰的研究增加了技术复杂性。该建议的目的是开发新的，更好的方法来检测和量化这些修改，然后使用这些方法来研究这些修饰的发生，调节和功能。 公共卫生相关性：该建议旨在开发化学和生化工具来研究新型蛋白酰基赖氨酸的修饰。这些酰基赖氨酸的修饰最近在我们的实验室中发现，与赖氨酸乙酰化在结构上不同，这是已知的 控制众多的生物途径并被认为是重要的药物靶标。拟议的研究将提供对代谢和蛋白质调节化学的基本理解，最终将促进新的治疗剂治疗人类疾病。