Investigation of the catalytic mechanism of farnesyl pyrophosphate synthase by computer simulation

V M SANCHEZ; A CRESPO; J. S. GUTKIND; A. G. TRUJANSKI

JOURNAL OF PHYSICAL CHEMISTRY B

American Chemical Society

Año: 2006 vol. 110 p. 18052 - 18057

1089-5647

Farnesyl pyrophosphate synthase (FPPS) catalyses the formation of a key cellular intermediate in isoprenoidmetabolic pathways, farnesyl pyrophosphate, by the sequential head-to-tail condensation of two molecules ofisopentenyl diphosphate (IPP) with dimethylallyl diphosphate (DMAPP). Recently, FPPS has been shown torepresent an important target for the treatment of parasitic diseases such as Chagas disease and Africantrypanosomiasis. Bisphosphonates, pyrophosphate analogues in which the oxygen bridge between the twophosphorus atoms has been replaced by a carbon substituted with different side chains, are able to inhibit theFPPS enzyme. Moreover, nitrogen-containing bisphosphonates have been proposed as carbocation transitionstate analogues of FPPS. On the basis of structural and kinetic data, different catalytic mechanisms havebeen proposed for FPPS. By analyzing different reaction coordinates we propose that the reaction occurs inone step through a carbocationic transition state and the subsequent transfer of a hydrogen atom from IPP tothe pyrophosphate moiety of DMAPP. Moreover, we have analyzed the role of the active site amino acids onthe activation barrier and the reaction mechanism. The structure of the active site is well conserved in theisoprenyl diphosphate synthase family; thus, our results are relevant for the understanding of this importantclass of enzymes and for the design of more potent and specific inhibitors for the treatment of parasiticdiseases.