Chemical Probes to Study Formaldehyde Biology

项目摘要/摘要 甲醛(FA)是一种普遍存在的小分子，它发挥着多种重要的 在人类健康和疾病中的作用。作为最简单的醛和活性羰基 物种，FA是一种主要的环境毒素，被归类为致癌物质，而FA 接触也与其他各种严重的疾病有关，从慢性 从肝脏疾病到癌症、心血管和神经退行性疾病以及糖尿病。 同时，人体在正常情况下会产生这种活性碳基物种。 生理学，主要是通过酶去甲基化事件以及通过一个- 碳循环。我们寻求开发和应用用于选择性成像的新的化学试剂 以及生命系统中FA的蛋白质组学，以确定其分子来源和靶点， 我们的长期目标是了解这种反应性小分子是如何形成的，以及在何种背景下 对生理和疾病都有贡献。这个应用程序将重点放在新的 在生物模型中实现FA选择性分子成像研究的技术 脂肪酸的产生和代谢来源以及伴随的化学蛋白质组学方法 在FA代谢受损的遗传模型中确定FA的靶点。特定的 目标包括开发用于FA亚细胞成像的新荧光探针和 应用基于活性的无偏蛋白质图谱(ABPP)的酶催化氧化合成甲酸盐 方法在整个蛋白质组中鉴定FA的半胱氨酸衍生靶点，并进行 生物化学和细胞学研究破译FA靶标在调节一碳中的作用 新陈代谢。

Project Summary/Abstract Formaldehyde (FA) is a ubiquitous small molecule that plays a diverse array of important roles in human health and disease. As the simplest aldehyde and reactive carbonyl species, FA is a major environmental toxin that is classified as a carcinogen, and FA exposure is also connected to a variety of other serious diseases ranging from chronic liver disorders to cancer, cardiovascular and neurodegenerative diseases, and diabetes. At the same time, the body produces this reactive carbonyl species during normal physiology, primarily through enzymatic demethylation events as well as through the one- carbon cycle. We seek to develop and apply new chemical reagents for selective imaging and proteomics of FA in living systems to identify its molecular sources and targets, with the long-term goal of understanding how and in what context this reactive small molecule contributes to both physiology and disease. This application will focus on new technologies to enable selective molecular imaging of FA in biological models to study sources of FA generation and metabolism, with accompanying chemoproteomics methods to identify targets of FA in genetic models where FA metabolism is compromised. Specific aims include developing new fluorescent probes for subcellular imaging of FA and enzymatic oxidation to formate, applying unbiased activity-based protein profiling (ABPP) methods to identify cysteine-derived targets of FA in whole proteomes, and performing biochemical and cellular studies to decipher roles of FA targets in regulating one-carbon metabolism.