CAREER: Spectroscopic/Computational Insights into the Biosynthesis and Reactivity of Adenosylcobalamin

University Of Wisconsin-Madison, Madison WI

Investigators

Abstract

The B12 cofactor adenosylcobalamin has long fascinated chemists with its unparalleled structural complexity and unusual reactivity in biological systems, involving homolytic cleavage of the organometallic Co-C bond. The goals of this CAREER project are to develop molecular-level understanding of the mechanism by which the adenosyltransferase from Salmonella enterica catalyzes the Co-C bond formation and to explore the mechanism by which the adenosylcobalamin -dependent isomerase methylmalonyl-CoA mutase from Proprionibacterium shermanii accelerates the rate of homolytic Co-C bond cleavage by 12 orders of magnitude without significantly enhancing undesired Co-C bond heterolysis. These goals will be accomplished by using a combination of spectroscopic methods (electronic absorption, circular dichroism, magnetic circular dichroism, resonance Raman, and electron paramagnetic resonance) and computational techniques (density functional theory and combined quantum mechanics/molecular mechanics approaches) to study free and enzyme-bound adenosylcobalamin and derivatives thereof. The educational plan is to develop and implement a series of interactive projects aimed at guiding student exploration of key chemical concepts in symmetry, bonding, and inorganic electronic spectroscopy. The Kolb model, a well-researched student-centered teaching model, will serve as the framework for incorporating both spectroscopic data collection and Mathcad-based interactive projects into graduate and upper-level undergraduate classrooms. Research in the interdisciplinary field of bioinorganic spectroscopy readily facilitates the development of a collaborative learning environment, in which students with diverse backgrounds share and communicate their individual expertise. The linking of research to applied chemistry provides a template for students attempting to bridge the gap between classroom and laboratory settings. Through integration of research-oriented problems into the classroom, new techniques and exercises engendering student involvement in the teaching process will be developed. Together, the research and educational projects outlined in this project would foster the breadth of experience, depth of knowledge, and communication skills crucial to the development of young scientists. This project is supported by the Molecular Biophysics Program in the Division of Molecular and Cellular Biosciences in the Directorate for Biological Sciences and the Inorganic, Bioinorganic and Organometallic Chemistry Program in the Division of Chemistry in the Mathematical and Physical Sciences Directorate.