The Search for the Mechanism of the Reaction Catalyzed by Farnesyltransferase

An experimental study was conducted to fully characterize the mechanism of the reaction catalyzed by FTase (farnesyltransferase) by determining the first real quantum chemistry transition-state structure for the concerted reaction catalyzed this enzyme. This was done using a 72-atom quantum-mechanical active-site model that includes the full zinc coordination sphere, an ethane thiolate to represent the CAAX cysteine residue, the pyrophosphate moiety, and the first isoprenoid subunit of FPP (farnesyldiphosphate). Special care was taken to accurately account for the effect of the enzyme, by including all the main specific interactions between the enzyme, the two model substrate and the metal coordination sphere. The results indicate a FPP(C1)-S(CAAX) distance of 2.955 Å and a C1-O(FPP) bond length of 1.779 Å for the transition state structure. A comparison of the values for the reactants and transition state show that the charge at the FPP C1 and C2 increases from the reactants to the transition state, whereas negative charges form on zinc bound sulfur atom and pyrophosphate oxygen atoms.