Research Abstracts Online
2008 - March 2009
University of Minnesota Twin Cities
Institute of Technology
Department of Chemistry
PI: Mark D. Distefano
The Evaluation of the Transition State of Farnesylation Reaction Via Kinetic Isotope Effect Modeling
Protein farnesyl transferase (PFTase) is an enzyme involved in post-translational modification of Ras proteins. The inhibition of PFTase prevents tumor cell growth, so PFTase inhibitors can be efficient anti-cancer drugs. Since the enzyme binds transition state (TS) much more tightly than substrate, TS analogs can be the most potent inhibitors. TS analogs can be designed if the structure of the TS in enzymatic reaction is known. These researchers are interested in determining the TS structure for the reaction catalyzed by PFTase.
The kinetic isotope effects (KIEs) reflect the structure of the TS. Thus, comparing the KIEs computed for the enzymatic reaction model and KIEs experimentally measured in enzymatic reaction allows one to find a structure that best resembles the TS. Using Gaussian, these researchers are optimizing a set of structures using different levels of theory, calculating the KIEs for each structure, and building the maps of electrostatic potential. This approach allows researchers to calculate the electron density map of the transition state of the enzymatic farnesylation reaction and provide insight for the design of putative anticancer drugs.
Amanda DeGraw, Graduate Student
Ben Duckworth, Graduate Student
Olivier Henry, Research Associate
Kelly Kyro, Graduate Student
Stepan Lenevich, Graduate Student