Chemistry without Cofactors: Discovering How a Protein Environment Facilitates Important Reactions with Oxygen

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Metabolism of food by cells occurs over a long and elaborate series of steps inside our cells, which is, in essence, similar to the chemical reaction known as combustion, in which the carbon compounds combine with oxygen gas (O2), to yield carbon dioxide, water, and large amounts of energy. The "flint", hidden inside proteins, consists of small metal-containing or vitamin-like compounds called cofactors, which bind the O2 molecule and begin to break apart its chemical bonds. The partially dismantled oxygen molecule is then ready to combine with carbon-containing molecules from food, releasing vast amounts of energy. In this way, cofactors allow nature to harness and control the power of atmospheric O2. The main objective of this project is to investigate a surprising variation on this process. Recently discovered proteins catalyze reactions between carbon-containing molecules and O2 without the help of cofactors. This project examines how these proteins effectively generate "fire without flint" or energy without cofactors. This project also examines an important potential biotechnological application of these proteins. A cofactor-free, protein-based catalyst can be easily grown in bacterial cultures without the need for the expensive added ingredients or elaborate biochemical pathways needed for assembling cofactors into proteins. These biocatalysts moreover offer clean, byproduct-free alternatives to existing chemical methods for carrying out similar processes. This project specifically examines how cofactor-free proteins can efficiently convert the abundant, renewable plant polymer known as lignin into starting materials for the production of bioplastics. This project will train K through 8 teachers and help develop a course about teaching teachers on issues of sustainability and science education. Research training and education of graduate and undergraduate students will also be supported by this project.O2 is an ideal oxidant because of its thermodynamic power, abundance, and the benign nature of its by-products. However, O2 possesses unpaired electron spins, making reactions between O2 and organic molecules impractically slow unless a catalyst is present. Biological catalysis of reactions with O2 generally depends on cofactors. The requirement for cofactors to mediate O2 biocatalysis is generally considered absolute. However, bacterial enzymes that catalyze diverse reactions between O2 and organic species in the complete absence of cofactors have recently been discovered. The main objective for this project, which focuses on a large family of cofactor-independent enzymes, is to determine how the protein environment alone activates O2 and steers the activated species toward the formation of specific products. This objective integrates experiment with several levels of theory. This project is supported jointly by the Molecular Biophysics Cluster of the Molecular and Cellular Biosciences Division in the Directorate for Biological Sciences and Chemistry for Life Processes Program of the Chemistry Division in the Directorate of Mathematical and Physical Sciences.