Chemical/biochemical tools for studying novel protein acyl lysine modifications

描述(申请人提供)：蛋白质翻译后修饰对调节蛋白质功能很重要，并参与许多生物过程。蛋白质乙酰化由乙酰基转移酶和脱乙酰基酶控制，在转录和代谢调节中起着重要作用。乙酰供体，乙酰辅酶A，是细胞内的代谢中间体。最近，我们实验室发现了几种新的酰基赖氨酸修饰，它们在结构上与乙酰基非常不同。我们已经证明，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)可以有效地去除它们。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产物，提示这些修饰可能是一种感知代谢调节蛋白质功能的机制。研究这些新的修饰将使我们更好地理解生物系统的化学。这项研究有可能为蛋白质乙酰化领域的一些谜题提供答案，例如大约一半的蛋白质去乙酰基酶缺乏酶活性。因为这些酰基赖氨酸的修饰以前没有被研究过，所以没有可用的工具来研究它们。多个酰基赖氨酸修饰的存在也为这些修饰的研究增加了一层技术复杂性。这项建议的目标是开发新的更好的方法来检测和量化这些修饰，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：该提案旨在开发化学和生化工具来研究新的蛋白质酰基赖氨酸修饰。这些酰基赖氨酸修饰是我们实验室最近发现的，在结构上不同于已知的赖氨酸乙酰化。 控制众多的生物途径，被认为是重要的药物靶点。这项拟议的研究将提供对新陈代谢和蛋白质调节化学的基本理解，最终将促进治疗人类疾病的新疗法的发展。

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.