CAREER: Harnessing Large Protein Conformational Changes to Perform Remarkable Chemical Reactions

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With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Markos Koutmos from the University of Michigan Ann Arbor to investigate how biological catalysts accomplish "unusual" or "improbable" chemical reactions. Vitamin B12 dependent methionine synthase (MS) is one nature's best catalysts, playing an integral role in the formation of methionine, one of the 20 commonly occurring amino acids that form proteins. MS catalyzes, or speeds up, a reaction that would be impossible under normal conditions (e.g., temperature, pressure, concentration). The Koutmos lab uses a combination of techniques, such as three-dimensional structure determinations and electron microscopy, along with reaction rate measurements, to understand how the enzyme is able to accomplish such a challenging reaction. The ultimate goal of this research is to use the enzyme as a chemical tool: reprogramming MS to catalyze novel, desired reactions for synthetic applications. This project is integrated into a public engagement program to enhance visual communication and general scientific literacy in high school and undergraduate students in cooperation with the University of Michigan Museum of Natural History. Collaboration with Fisk University chemists involves under-represented minority students in research projects at the University of Michigan during the summer.This research project seeks to uncover fundamental principles regarding how enzyme dynamics facilitate challenging chemical reactions and, ultimately, to exploit these principles in order to reprogram biological enzymes to catalyze new reactions. Transient kinetic and structural biology approaches establish how MS module arrangements support three distinct methyl transferase reactions. The information gained from the mechanistic studies informs the design of engineered MS-based proteins and unnatural/synthetic cobalamin analogs to create a customizable biocatalytic system to direct the reactivity of MS to catalyze methylations, or even alkylations, on noncanonical substrates. MS is highly flexible and contains extensive interdomain interfaces that are assembled and disassembled as needed to support the chemical reactions. This research establishes how stochastic motions, the oxidation state, and coordination environment of the cobalamin cofactor contribute to the dynamics of conformational states accessible to the enzyme. Information from this study provides insight into how large multi-modular enzymes rearrange to accomplish their reactions. The research has the potential to open a new area of research into how methyltransferases can be redesigned to address the need of chemists to efficiently and specifically transfer methyl-groups.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.