Bisphosphonates target multiple sites in both cis- and trans- prenyltransferases

Rey Ting Guo, Rong Cao, Po Huang Liang, Tzu Ping Ko, Tao Hsin Chang, Michael P. Hudock, Wen Yih Jeng, Cammy K.M. Chen, Yonghui Zhang, Yongcheng Song, Chih Jung Kuo, Fenglin Yin, Eric Oldfield, Andrew H.J. Wang

Research output: Contribution to journalArticlepeer-review

142 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)10022-10027
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number24
DOIs
Publication statusPublished - Jun 12 2007
Externally publishedYes

Keywords

  • Cell wall
  • Geranylgeranyl diphosphate synthase
  • Undecaprenyl diphosphate synthase
  • X-ray structure

ASJC Scopus subject areas

  • General

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