Skip Header

You are using a version of browser that may not display all the features of this website. Please consider upgrading your browser.

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

Guo R.-T., Cao R., Liang P.-H., Ko T.-P., Chang T.-H., Hudock M.P., Jeng W.-Y., Chen C.K.-M., Zhang Y., Song Y., Kuo C.-J., Yin F., Oldfield E., Wang A.H.-J.

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.

Proc. Natl. Acad. Sci. U.S.A. 104:10022-10027(2007) [PubMed] [Europe PMC]

We'd like to inform you that we have updated our Privacy Notice to comply with Europe’s new General Data Protection Regulation (GDPR) that applies since 25 May 2018.

Do not show this banner again
UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health