Bisphosphonates Target Multiple Sites in Both Cis- and Trans-prenyltransferases

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2007 May 31

PMID 17535895

Citations 84

Authors

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

Affiliations

Soon will be listed here.

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.

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