Sousa Sérgio Filipe, Fernandes Pedro Alexandrino, Ramos Maria João
REQUIMTE, Departamento de Química, Faculdade de Ciências, Universidade do Porto, 4169-007 Porto, Portugal.
Proteins. 2007 Jan 1;66(1):205-18. doi: 10.1002/prot.21219.
In spite of the enormous interest that has been devoted to its study, the mechanism of the enzyme farnesyltransferase (FTase) remains the subject of several crucial doubts. In this article, we shed a new light in one of the most fundamental dilemmas that characterize the mechanism of this puzzling enzyme commonly referred to as the "distances paradox", which arises from the existence of a large 8-A distance between the two reactive atoms in the reaction catalyzed by this enzyme: a Zn-bound cysteine sulphur atom from a peptidic substrate and the farnesyldiphosphate (FPP) carbon 1. This distance must be overcome for the reaction to occur. In this study, the two possible alternatives were evaluated by combining molecular mechanics (AMBER) and quantum chemical calculations (B3LYP). Basically, our results have shown that an activation of the Zn-bound cysteine thiolate with subsequent displacement from the zinc coordination sphere towards the FPP carbon 1 is not a realistic hypothesis of overcoming the large distance reported in the crystallographic structures of the ternary complexes between the two reactive atoms, but that a rotation involving the FPP molecule can bring the two atoms closer with moderate energetic cost, coherent with previous experimental data. This conclusion opens the door to an understanding of the chemical step in the farnesylation reaction.
