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 journalArticle

120 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 - 2007 Jun 12

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undecaprenyl pyrophosphate synthetase
Diphosphonates
Farnesyltranstransferase
Geranyltranstransferase
Binding Sites
zoledronic acid
Prenylation
Alendronate
Monomeric GTP-Binding Proteins
Pharmaceutical Preparations
cis-prenyl transferase

All Science Journal Classification (ASJC) codes

  • General

Cite this

Guo, Rey Ting ; Cao, Rong ; Liang, Po Huang ; Ko, Tzu Ping ; Chang, Tao Hsin ; Hudock, Michael P. ; Jeng, Wen-Yih ; Chen, Cammy K.M. ; Zhang, Yonghui ; Song, Yongcheng ; Kuo, Chih Jung ; Yin, Fenglin ; Oldfield, Eric ; Wang, Andrew H.J. / Bisphosphonates target multiple sites in both cis- and trans- prenyltransferases. In: Proceedings of the National Academy of Sciences of the United States of America. 2007 ; Vol. 104, No. 24. pp. 10022-10027.
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author = "Guo, {Rey Ting} and Rong Cao and Liang, {Po Huang} and Ko, {Tzu Ping} and Chang, {Tao Hsin} and Hudock, {Michael P.} and Wen-Yih Jeng and Chen, {Cammy K.M.} and Yonghui Zhang and Yongcheng Song and Kuo, {Chih Jung} and Fenglin Yin and Eric Oldfield and Wang, {Andrew H.J.}",
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Guo, RT, Cao, R, Liang, PH, Ko, TP, Chang, TH, Hudock, MP, Jeng, W-Y, Chen, CKM, Zhang, Y, Song, Y, Kuo, CJ, Yin, F, Oldfield, E & Wang, AHJ 2007, 'Bisphosphonates target multiple sites in both cis- and trans- prenyltransferases', Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 24, pp. 10022-10027. https://doi.org/10.1073/pnas.0702254104

Bisphosphonates target multiple sites in both cis- and trans- prenyltransferases. / Guo, Rey Ting; Cao, Rong; Liang, Po Huang; Ko, Tzu Ping; Chang, Tao Hsin; Hudock, Michael P.; Jeng, Wen-Yih; Chen, Cammy K.M.; Zhang, Yonghui; Song, Yongcheng; Kuo, Chih Jung; Yin, Fenglin; Oldfield, Eric; Wang, Andrew H.J.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 104, No. 24, 12.06.2007, p. 10022-10027.

Research output: Contribution to journalArticle

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T1 - Bisphosphonates target multiple sites in both cis- and trans- prenyltransferases

AU - Guo, Rey Ting

AU - Cao, Rong

AU - Liang, Po Huang

AU - Ko, Tzu Ping

AU - Chang, Tao Hsin

AU - Hudock, Michael P.

AU - Jeng, Wen-Yih

AU - Chen, Cammy K.M.

AU - Zhang, Yonghui

AU - Song, Yongcheng

AU - Kuo, Chih Jung

AU - Yin, Fenglin

AU - Oldfield, Eric

AU - Wang, Andrew H.J.

PY - 2007/6/12

Y1 - 2007/6/12

N2 - 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.

AB - 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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