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Farnesyl pyrophosphate synthase is the molecular target of nitrogen-containing bisphosphonates

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Author: Beek, E. van · Pieterman, E. · Cohen, L. · Löwik, C. · Papapoulos, S.
Type:article
Date:1999
Institution: Gaubius instituut TNO
Source:Biochemical and Biophysical Research Communications, 1, 264, 108-111
Identifier: 235189
doi: doi:10.1006/bbrc.1999.1499
Keywords: Animals · Brain · Carbon Radioisotopes · Carbon-Carbon Double Bond Isomerases · Cattle · Dimethylallyltranstransferase · Diphosphonates · Enzyme Inhibitors · Indoles · Mevalonic Acid · Bovinae

Abstract

Bisphosphonates (Bps), inhibitors of osteoclastic bone resorption, are used in the treatment of skeletal disorders. Recent evidence indicated that farnesyl pyrophosphate (FPP) synthase and/or isopentenyl pyrophosphate (IPP) isomerase is the intracellular target(s) of bisphosphonate action. To examine which enzyme is specifically affected, we determined the effect of different Bps on incorporation of [14C]mevalonate (MVA), [14C]IPP, and [14C]dimethylallyl pyrophosphate (DMAPP) into polyisoprenyl pyrophosphates in a homogenate of bovine brain. HPLC analysis revealed that the three intermediates were incorporated into FPP and geranylgeranyl pyrophosphate (GGPP). In contrast to clodronate, the nitrogen-containing Bps (NBps), alendronate, risedronate, olpadronate, and ibandronate, completely blocked FPP and GGPP formation and induced in incubations with [14C]MVA a 3- to 5-fold increase in incorporation of label into IPP and/or DMAPP. Using a method that could distinguish DMAPP from IPP on basis of their difference in stability in acid, we found that none of the NBps affected the conversion of [14C]IPP into DMAPP, catalyzed by IPP isomerase, excluding this enzyme as target of NBp action. On the basis of these and our previous findings, we conclude that none of the enzymes up- or downstream of FPP synthase are affected by NBps, and FPP synthase is, therefore, the exclusive molecular target of NBp action. Chemicals/CAS: Carbon Radioisotopes; Carbon-Carbon Double Bond Isomerases, EC 5.3.3.-; Dimethylallyltranstransferase, EC 2.5.1.1; Diphosphonates; Enzyme Inhibitors; indolepropanol phosphate, 40716-80-1; Indoles; isopentenyldiphosphate delta-isomerase, EC 5.3.3.2; Mevalonic Acid, 150-97-0