Mechanism of aminobisphosphonate action: characterization of alendronate inhibition of the isoprenoid pathway.
Alendronate (ALN), an aminobisphosphonate compound used for the treatment of osteoporosis and other disorders of bone resorption, has been suggested to act by inhibition of the formation of GGPP. In the present study we used an S(10) homogenate fraction of rat liver to show that ALN causes a dose-dependent inhibition of [(3)H]MVA incorporation into sterols and a concomitant increase in incorporation of radiolabel into IPP and DMAPP. We further show that ALN is a potent inhibitor of cytosolic trans-prenyltransferase (FPP synthase). The inhibition is competitive with respect to allylic pyrophosphate substrates, but not IPP, suggesting that ALN acts as an allylic pyrophosphate analog and binds to the free enzyme. The K(i) is in the 0.5 microM range.
Keller
R K
RK
Department of Biochemistry and Molecular Biology, University of South Florida, Tampa, Florida 33612, USA.
Fliesler
S J
SJ
D019386:Alendronate / Q000494:pharmacology*; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003600:Cytosol / Q000201:enzymology / Q000378:metabolism; D051228:Geranyltranstransferase; D045782:Hemiterpenes; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008798:Mevalonic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000378:metabolism; D011106:Polyisoprenyl Phosphates / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012717:Sesquiterpenes
D045782:Hemiterpenes; D009943:Organophosphorus Compounds; D011106:Polyisoprenyl Phosphates; D012717:Sesquiterpenes; C004809:isopentenyl pyrophosphate; C043060:3,3-dimethylallyl pyrophosphate; C004808:farnesyl pyrophosphate; D019883:Alkyl and Aryl Transferases; D051228:Geranyltranstransferase; D008798:Mevalonic Acid; D019386:Alendronate