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Digeranyl bisphosphonate inhibits geranylgeranyl pyrophosphate synthase
Andrew J Wiemer1, Huaxiang Tong, Kelly M Swanson
1Molecular and Cellular Biology Interdisciplinary Program, Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA. Andrew-Wiemer@uiowa.edu
Abstract:
A primary cellular target of the clinical nitrogenous bisphosphonates is the isoprenoid biosynthetic pathway. Specifically these drugs inhibit the enzyme farnesyl pyrophosphate synthase and deplete cells of larger isoprenoids. Inhibition of this enzyme results in impaired processing of both farnesylated and geranylgeranylated proteins. We recently showed that isoprenoid-containing bisphosphonates such as digeranyl bisphosphonate inhibit protein geranylgeranylation and not farnesylation. Here, we show that this impairment results from potent and specific inhibition of geranylgeranyl pyrophosphate synthase, which leads to enhanced depletion of intracellular geranylgeranyl pyrophosphate relative to the nitrogenous bisphosphonate zoledronate.
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