Bisphosphonates target multiple sites in both cis- and trans-prenyltransferases.
Article Details
- CitationCopy to clipboard
Guo RT, Cao R, Liang PH, Ko TP, Chang TH, Hudock MP, Jeng WY, Chen CK, Zhang Y, Song Y, Kuo CJ, Yin F, Oldfield E, Wang AH
Bisphosphonates target multiple sites in both cis- and trans-prenyltransferases.
Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10022-7. Epub 2007 May 29.
- PubMed ID
- 17535895 [ View in PubMed]
- Abstract
Bisphosphonate drugs (e.g., Fosamax and Zometa) are thought to act primarily by inhibiting farnesyl diphosphate synthase (FPPS), resulting in decreased prenylation of small GTPases. Here, we show that some bisphosphonates can also inhibit geranylgeranyl diphosphate synthase (GGPPS), as well as undecaprenyl diphosphate synthase (UPPS), a cis-prenyltransferase of interest as a target for antibacterial therapy. Our results on GGPPS (10 structures) show that there are three bisphosphonate-binding sites, consisting of FPP or isopentenyl diphosphate substrate-binding sites together with a GGPP product- or inhibitor-binding site. In UPPS, there are a total of four binding sites (in five structures). These results are of general interest because they provide the first structures of GGPPS- and UPPS-inhibitor complexes, potentially important drug targets, in addition to revealing a remarkably broad spectrum of binding modes not seen in FPPS inhibition.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Alendronic acid Farnesyl pyrophosphate synthase Protein Humans YesInhibitorDetails Ibandronate Geranylgeranyl pyrophosphate synthase Protein Humans YesInhibitorDetails Minodronic acid Geranylgeranyl pyrophosphate synthase Protein Humans YesInhibitorDetails Zoledronic acid Farnesyl pyrophosphate synthase Protein Humans YesInhibitorDetails Zoledronic acid Geranylgeranyl pyrophosphate synthase Protein Humans YesInhibitorDetails - Polypeptides
Name UniProt ID Ditrans,polycis-undecaprenyl-diphosphate synthase ((2E,6E)-farnesyl-diphosphate specific) P60472 Details - Binding Properties
Drug Target Property Measurement pH Temperature (°C) [2-(3-DIBENZOFURAN-4-YL-PHENYL)-1-HYDROXY-1-PHOSPHONO-ETHYL]-PHOSPHONIC ACID Geranylgeranyl pyrophosphate synthase IC 50 (nM) 4000 N/A N/A Details [2-(3-DIBENZOFURAN-4-YL-PHENYL)-1-HYDROXY-1-PHOSPHONO-ETHYL]-PHOSPHONIC ACID Geranylgeranyl pyrophosphate synthase Ki (nM) 110 N/A N/A Details Zoledronic acid Geranylgeranyl pyrophosphate synthase IC 50 (nM) 97000 N/A N/A Details Zoledronic acid Geranylgeranyl pyrophosphate synthase Ki (nM) 2700 N/A N/A Details