title: Correlation between time-dependent inhibition of human farnesyl pyrophosphate synthase and blockade of mevalonate pathway by nitrogen-containing bisphosphonates in cultured cells.
abstract: A class of drugs successfully used for treatment of metabolic bone diseases is the nitrogen-containing bisphosphonates (N-BPs), which act by inhibiting the vital enzyme, farnesyl pyrophosphate synthase (FPPS), of the mevalonate pathway. Inhibition of FPPS by N-BPs results in the intracellular accumulation of isopentenyl pyrophosphate (IPP) and consequently induces the biosynthesis of a cytotoxic ATP analog (ApppI). Previous cell-free data has reported that N-BPs inhibit FPPS by time-dependent manner as a result of the conformational change. This associated conformational change can be measured as an isomerization constant (K(isom)) and reflects the binding differences of the N-BPs to FPPS. In the present study, we tested the biological relevance of the calculated K(isom) values of zoledronic acid, risedronate and five experimental N-BP analogs in the cell culture model. We used IPP/ApppI formation as a surrogate marker for blocking of FPPS in the mevalonate pathway. As a result, a correlation between the time-dependent inhibition of FPPS and IPP/ApppI formation by N-BPs was observed. This outcome indicates that the time-dependent inhibition of FPPS enzyme is a biologically significant mechanism and further supports the use of the K(isom) calculations for evaluation of the overall potency of the novel FPPS inhibitors. Additionally, data illustrates that IPP/ApppI analysis is a useful method to monitor the intracellular action of drugs and drug candidates based on FPPS inhibition.
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland. johanna.raikkonen@uef.fi
authors.forename: Johanna
authors.initials: J
authors.lastname: Räikkönen
authors.forename: Markku
authors.initials: M
authors.lastname: Taskinen
authors.forename: James E
authors.initials: JE
authors.lastname: Dunford
authors.forename: Hannu
authors.initials: H
authors.lastname: Mönkkönen
authors.forename: Seppo
authors.initials: S
authors.lastname: Auriola
authors.forename: Jukka
authors.initials: J
authors.lastname: Mönkkönen
mesh_terms: D002478:Cells, Cultured; D004122:Dimethylallyltranstransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004164:Diphosphonates / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008798:Mevalonic Acid / Q000378:metabolism*; D009584:Nitrogen / Q000737:chemistry; D013997:Time Factors
chemical_list: D004164:Diphosphonates; D004122:Dimethylallyltranstransferase; D009584:Nitrogen; D008798:Mevalonic Acid