Unfolding Noncanonical Functions of Lysine Acetyltransferases

凭借这一奖项，化学学部的生命过程化学项目将资助乔治亚大学的Y. George Zheng博士研究一种名为KATs的酶的新功能。以前，已知KATs的作用以一种开-关的方式控制基因。最近的发现揭示了除了对基因的影响之外，KATs几乎在细胞的每个地方都有新的生物学作用。KATs的功能比以前认为的要复杂得多，它影响多方面的生物过程，包括促进全新的化学反应。在这个项目中，PI设计了一系列的生化和细胞实验研究，以发现和表征主要KAT酶的新功能。提出了一种高度多学科的方法来解剖新的KAT功能。这种追求与PI在培养化学生物学和生物化学方面的研究生和本科生方面的努力直接相关。通过承担这些项目，学生将学习如何应用先进技术来解决关键的生物学研究问题。该项目还整合了向高中生介绍酶生物化学科学的外展活动。这些与研究相关的教育工作对于培养下一代化学和生物科学科学家非常重要。该研究项目致力于开发和应用新的化学生物学工具来分析细胞底物和主要KAT酶的新功能，旨在显著推进蛋白质酰化研究。PI改进并应用生物正交标记技术在蛋白质组学水平上研究主要KATs的底物概况。PI及其同事还研究了他们最近在组蛋白和非组蛋白中发现的一种新的赖氨酸酰化标记。在这些实验中，研究小组确定了催化新修饰标记的添加和去除的酶。本研究为KAT活性研究提供了新的化学工具，提供了KAT底物在细胞中的分布的系统视图，提供了KAT功能的机制理解，并在更广泛的层面上推进了对染色质重塑、代谢途径和信号转导的翻译后修饰的认识。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Y. George Zheng from University of Georgia to investigate novel functions of enzymes called KATs. Previously the actions of KATs were known to control genes in an on-off fashion. Recent discoveries revealed new biological roles for KATs nearly every place in the cell, beyond the effect on genes. Functions of KATs are far more complex than previously regarded with impacts on multifaceted biological processes, including promoting entirely new chemical reactions. In this project, the PI designed a series of biochemical and cellular experimental studies to discover and characterize new functions of the major KAT enzymes. A highly multidisciplinary approach is proposed to dissect novel KAT functions. This pursuit is directly related to the PI's efforts in the training of graduate and undergraduate students in chemical biology and biochemistry. By undertaking these projects, students will learn how to apply advanced technologies to resolve key biological research problems. This project also integrates outreach activities to introduce high school students to the science of enzyme biochemistry. These research-related educational efforts are important to prepare next-generation scientists in chemical and biological sciences.The research project undertakes the development and application of new chemical biology tools to profile cellular substrates and new functions of the major KAT enzymes, with the goal of significantly advancing protein acylation research. The PI refines and applies a bioorthogonal labeling technology to investigate substrate profiles of the major KATs at the proteomic level. The PI and coworkers also investigate a novel lysine acylation mark in histones and non-histone proteins that they recently discovered. In these experiments, the team identifies enzymes that catalyze the addition and removal of the novel modification mark. The proposed research has great potential to generate new chemical tools for KAT activity investigation, offers a systematic view of KAT substrate distribution in the cell, provides a mechanistic understanding of KAT functions, and to a broader level, advances the knowledge of posttranslational modifications in chromatin remodeling, metabolic pathways, and signal transduction.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.