Digeranyl bisphosphonate inhibits geranylgeranyl pyrophosphate synthase.
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.
Wiemer
Andrew J
AJ
Molecular and Cellular Biology Interdisciplinary Program, Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA. Andrew-Wiemer@uiowa.edu
Tong
Huaxiang
H
Swanson
Kelly M
KM
Hohl
Raymond J
RJ
D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004164:Diphosphonates / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005434:Flow Cytometry; D051232:Geranylgeranyl-Diphosphate Geranylgeranyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051228:Geranyltranstransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D011106:Polyisoprenyl Phosphates / Q000378:metabolism; D017368:Protein Prenylation / Q000187:drug effects; D013729:Terpenes / Q000737:chemistry / Q000494:pharmacology*; D000077211:Zoledronic Acid
D004164:Diphosphonates; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011106:Polyisoprenyl Phosphates; D013729:Terpenes; C518651:digeranyl bisphosphonate; D000077211:Zoledronic Acid; D051228:Geranyltranstransferase; D051232:Geranylgeranyl-Diphosphate Geranylgeranyltransferase; C002963:geranylgeranyl pyrophosphate