Redox Photochemistry of Oxidized Bases in DNA and RNA

通过这一奖项，化学部的生命过程化学计划资助犹他大学的Cynthia J.Burrow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，然而自然产生的氨基酸并不是非常具有氧化还原活性。为了进行还原或氧化反应，酶依赖于辅酶，如维生素B2(核黄素)、B3(烟酰胺)或B12(钴胺)。有趣的是，这些辅酶都是RNA的衍生物，通常是由腺苷和氧化还原活性杂环组成的二核苷酸。被支持的项目将检验这样一种假设，即自然产生的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。这些修饰的碱基将是最小的核酶或脱氧核酶结构的组成部分，反应将在光中启动。在布伦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相结合的研究，同时测试关于早期地球或其他星球上简单的生物聚合物产生生命的潜在方式的假说。在这个项目中，研究人员将使用有机合成和寡核苷酸组装来研究由黄素和黄素样杂环(包括8-氧鸟嘌呤)介导的催化氧化还原反应。将设计和合成能够自组装成包含核苷酸辅助因子结合位点的G-四链体的最小寡聚体。生物物理测量(核磁共振、CD、UV)将确定折叠结构和稳定性，并将辅之以纳米孔洞中G-四链体的单分子研究，以提供动力学稳定性和人口研究。这些富含嘌呤的络合物中电子转移反应的光物理将有助于理解为什么今天的杂环碱基被选为DNA和RNA，而其他碱基则被微调为氧化还原核糖核酸辅因子。这项工作将为系统化学方法如何帮助解释早期生命的出现提供洞察力。

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.