Nitrogen-containing bisphosphonates inhibit isopentenyl pyrophosphate isomerase/farnesyl pyrophosphate synthase activity with relative potencies corresponding to their antiresorptive potencies in vitro and in vivo.
Bisphosphonates, synthetic compounds which suppress bone resorption, are used in the treatment of skeletal disorders. Their mode of action and intracellular targets have not yet been identified. Recent evidence suggested that enzymes of the mevalonate pathway are the potential targets. In this study, we examined the effect of four potent nitrogen (N)-containing bisphosphonates, clodronate and NH2-olpadronate, an inactive analogue of olpadronate, on isopentenyl pyrophosphate isomerase/farnesyl pyrophosphate synthase, geranylgeranyl pyrophosphate synthase, and protein geranylgeranyl transferase I activity. We found that all N-containing bisphosphonates inhibited isopentenyl pyrophosphate isomerase/farnesyl pyrophosphate synthase activity dose dependently with relative potencies corresponding to their antiresorptive potencies in vitro and in vivo, whereas clodronate and NH2-olpadronate had no effect. Furthermore, none of the bisphosphonates tested affected geranylgeranyl pyrophosphate synthase or geranylgeranyl transferase I activity. Our study reveals for the first time the intracellular target of N-containing bisphosphonates and supports the view that all bisphosphonates do not share the same molecular mechanism of action.
Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, The Netherlands. E.R.van_Beek@EndoCrinology.Medfac.LeidenUniv.NL
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van Beek
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Pieterman
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Cohen
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Löwik
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Papapoulos
D000818:Animals; D001862:Bone Resorption / Q000201:enzymology*; D001921:Brain / Q000201:enzymology; D019748:Carbon-Carbon Double Bond Isomerases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002417:Cattle; D004002:Clodronic Acid / Q000494:pharmacology; D004122:Dimethylallyltranstransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004164:Diphosphonates / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D045782:Hemiterpenes; D000077557:Ibandronic Acid; D051379:Mice; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009584:Nitrogen; D000077268:Pamidronate
D004164:Diphosphonates; D004791:Enzyme Inhibitors; D045782:Hemiterpenes; D009097:Multienzyme Complexes; D004002:Clodronic Acid; C055774:olpadronic acid; D004122:Dimethylallyltranstransferase; D019748:Carbon-Carbon Double Bond Isomerases; C021453:isopentenyldiphosphate delta-isomerase; D009584:Nitrogen; D000077268:Pamidronate; D000077557:Ibandronic Acid