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.
