NSF Award
1026788
This award in the Chemistry of Life Processes (CLP) program supports work by Professors Denis Rousseau and Syun-Ru Yeh at the Albert Einstein College of Medicine to carry out fundamental studies on the energy landscape that underlies the catalytic mechanism of two enzyme systems: nitric oxide synthase and indolamine dioxygenase. This research will be done as part of an International Collaboration in Chemistry (ICC) with Professor Uli Nienhaus at the University of Karlsruhe in Germany, whose work will be supported by the Deutsche Forschungsgemeinschaft (DFG). Nitric oxide synthase catalyzes the formation of the signaling molecule, nitric oxide, from L-arginine and oxygen; and indolamine dioxygenase regulates immune responses by oxidizing L-tryptophan to N-formylkynurenine. To determine the dynamic properties that modulate the energy landscapes of the enzymatic reactions of these two proteins, critical amino acid residues will be mutated and their structural and catalytic properties will be the studied by spectroscopic methods under equilibrium and kinetic conditions. The mutants will be sent to the Nienhaus lab in Karlsruhe for the dynamics measurements by temperature derivative Fourier transform infrared spectroscopy; the data thus generated will be compared to the basic structural and functional properties obtained at the Albert Einstein College of Medicine. The process will be repeated until a comprehensive understanding of the role of dynamics in these two enzymes is achieved. In order to obtain a sound foundation of the catalytic mechanisms, the data will be integrated by combined quantum mechanics and molecular mechanics calculations.<br/><br/>The collaboration will include visits by both groups to each other's lab to set the strategy for the research and evaluate the findings. These visits between the US and German groups will provide outstanding training opportunities to all of the students and postdoctoral fellows participating in this project. The research will reveal how the molecular dynamics of each enzyme dictate its functional properties and will therefore serve as a foundation for the development of therapeutic targets for these enzymes.
