Redox Photochemistry of Oxidized Bases in DNA and RNA

DNA 和 RNA 中氧化碱基的氧化还原光化学

• 批准号: 1507813
• 负责人: Cynthia Burrows
• 金额: $ 46.7万
• 依托单位: University of Utah
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1507813&HistoricalAwards=false
• 关键词: Redox; Photochemistry; Oxidized; Bases; DNA

With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Cynthia J. Burrows at the University of Utah to investigate the redox photochemistry of oxidized bases in DNA and RNA. Most chemical reactions inside the cell are catalyzed by proteins (enzymes), yet the naturally occurring amino acids are not very redox-active. To conduct reduction or oxidation reactions, enzymes rely on co-enzymes such as vitamins B2 (riboflavin), B3 (nicotinamide) or B12 (cobalamin). Interestingly, these co-enzymes are all derivatives of RNA, usually dinucleotides comprising adenosine plus a redox-active heterocycle. The project being supported will examine the hypothesis that simple oxidized derivatives of naturally occurring DNA or RNA bases can perform as redox cofactors to catalyze electron-transfer reactions. These modified bases will be components of minimal ribozyme or DNAzyme structures, and reactions will be initiated with light. Experiments conducted in the Burrows laboratory will be complemented by ultrafast spectroscopic measurements and computational work performed in collaboration. Graduate, undergraduate and high school students trained on the project will therefore be engaged in research at the interface of modern bioorganic and biophysical chemistry while testing hypotheses about potential ways in which life emerged from simple biopolymers on Early Earth or other planets.In this project, researchers will use organic synthesis and oligonucleotide assembly to study catalytic redox reactions mediated by flavins and flavin-like heterocycles including 8-oxoguanine. Minimal oligomers that can self-assemble into G-quadruplexes containing binding sites for nucleotide cofactors will be designed and synthesized. Biophysical measurements (NMR, CD, UV) will determine folded structures and stabilities, and will be complemented by single-molecule investigations of G-quadruplexes in nanopore cavities to provide kinetic stability and population studies. The photophysics of electron-transfer reactions within these purine-rich complexes will help in understanding why the present-day heterocyclic bases were chosen for DNA and RNA, while others have been fine-tuned as redox ribonucleotide cofactors. The work will provide insights into how a systems chemistry approach to chemical evolution might help explain the emergence of early life.

凭借该奖项，化学部的生命过程化学项目将资助犹他大学的 Cynthia J. Burrows 博士研究 DNA 和 RNA 中氧化碱基的氧化还原光化学。 细胞内的大多数化学反应都是由蛋白质（酶）催化的，但天然存在的氨基酸的氧化还原活性并不强。 为了进行还原或氧化反应，酶依赖于维生素 B2（核黄素）、B3（烟酰胺）或 B12（钴胺素）等辅酶。 有趣的是，这些辅酶都是RNA的衍生物，通常是包含腺苷加上氧化还原活性杂环的二核苷酸。 所支持的项目将检验以下假设：天然存在的 DNA 或 RNA 碱基的简单氧化衍生物可以作为氧化还原辅助因子来催化电子转移反应。 这些修饰的碱基将成为最小核酶或脱氧核糖核酸酶结构的组成部分，并且反应将由光引发。 在巴罗斯实验室进行的实验将得到超快光谱测量和合作进行的计算工作的补充。 因此，接受过该项目培训的研究生、本科生和高中生将从事现代生物有机化学和生物物理化学交叉领域的研究，同时测试有关早期地球或其他行星上简单生物聚合物中生命出现的潜在方式的假设。研究人员将利用有机合成和寡核苷酸组装来研究黄素和类黄素杂环（包括 8-氧代鸟嘌呤）介导的催化氧化还原反应。 将设计并合成可自组装成含有核苷酸辅因子结合位点的 G 四链体的最小寡聚物。 生物物理测量（NMR、CD、UV）将确定折叠结构和稳定性，并将辅以纳米孔腔中 G-四链体的单分子研究，以提供动力学稳定性和群体研究。 这些富含嘌呤复合物内电子转移反应的光物理学将有助于理解为什么当今的杂环碱基被选择用于 DNA 和 RNA，而其他碱基则被微调为氧化还原核糖核苷酸辅助因子。 这项工作将深入探讨化学演化的系统化学方法如何帮助解释早期生命的出现。