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.
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.
|Bheda, Poonam; Jing, Hui; Wolberger, Cynthia et al. (2016) The Substrate Specificity of Sirtuins. Annu Rev Biochem 85:405-29|
|Zhang, Xiaoyu; Khan, Saba; Jiang, Hong et al. (2016) Identifying the functional contribution of the defatty-acylase activity of SIRT6. Nat Chem Biol 12:614-20|
|Sadhukhan, Sushabhan; Liu, Xiaojing; Ryu, Dongryeol et al. (2016) Metabolomics-assisted proteomics identifies succinylation and SIRT5 as important regulators of cardiac function. Proc Natl Acad Sci U S A 113:4320-5|
|Liu, Xiaojing; Sadhukhan, Sushabhan; Sun, Shengyi et al. (2015) High-Resolution Metabolomics with Acyl-CoA Profiling Reveals Widespread Remodeling in Response to Diet. Mol Cell Proteomics 14:1489-500|
|He, Bin; Hu, Jing; Zhang, Xiaoyu et al. (2014) Thiomyristoyl peptides as cell-permeable Sirt6 inhibitors. Org Biomol Chem 12:7498-502|
|Colak, Gozde; Xie, Zhongyu; Zhu, Anita Y et al. (2013) Identification of lysine succinylation substrates and the succinylation regulatory enzyme CobB in Escherichia coli. Mol Cell Proteomics 12:3509-20|