The protein:farnesyl transferase catalytic mechanism of action will be determined. This enzyme catalyzes the farnesylation of Ras proteins, the mutant forms of which are found in 30% of human cancers. The approach will consist of: (A) determination of mechanism rate constants from steady state and rapid quench experiments; (B) examination of the nature of the chemical intermediate step from secondary substrate kinetic isotope effects; (C) examination of the nature of the bound peptide substrate from multiple quantum coherence NMR experiments. The results of this study will benefit the rational design of inhibitors d reaction intermediates.
