Investigation of the catalytic mechanism of farnesyl pyrophosphate synthase by computer simulation.
Farnesyl pyrophosphate synthase (FPPS) catalyses the formation of a key cellular intermediate in isoprenoid metabolic pathways, farnesyl pyrophosphate, by the sequential head-to-tail condensation of two molecules of isopentenyl diphosphate (IPP) with dimethylallyl diphosphate (DMAPP). Recently, FPPS has been shown to represent an important target for the treatment of parasitic diseases such as Chagas disease and African trypanosomiasis. Bisphosphonates, pyrophosphate analogues in which the oxygen bridge between the two phosphorus atoms has been replaced by a carbon substituted with different side chains, are able to inhibit the FPPS enzyme. Moreover, nitrogen-containing bisphosphonates have been proposed as carbocation transition state analogues of FPPS. On the basis of structural and kinetic data, different catalytic mechanisms have been proposed for FPPS. By analyzing different reaction coordinates we propose that the reaction occurs in one step through a carbocationic transition state and the subsequent transfer of a hydrogen atom from IPP to the pyrophosphate moiety of DMAPP. Moreover, we have analyzed the role of the active site amino acids on the activation barrier and the reaction mechanism. The structure of the active site is well conserved in the isoprenyl diphosphate synthase family; thus, our results are relevant for the understanding of this important class of enzymes and for the design of more potent and specific inhibitors for the treatment of parasitic diseases.
Sanchez
Verónica Muriel
VM
Departamento de Química Inorganica, Analítica y Química Física/INQUIMAE, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires/CONICET, Ciudad Universitaria, Pab. II, P. 3, C1428EHA Buenos Aires, Argentina.
Crespo
Alejandro
A
Gutkind
J Silvio
JS
Turjanski
Adrián Gustavo
AG
D000596:Amino Acids; D001665:Binding Sites; D002384:Catalysis; D003198:Computer Simulation; D051228:Geranyltranstransferase / Q000378:metabolism*; D006859:Hydrogen / Q000737:chemistry; D013729:Terpenes / Q000378:metabolism
D000596:Amino Acids; D013729:Terpenes; D006859:Hydrogen; D051228:Geranyltranstransferase