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

doi:10.1073/pnas.0702254104

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 journal › Article › peer-review

156 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 language	English
Pages (from-to)	10022-10027
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	104
Issue number	24
DOIs	https://doi.org/10.1073/pnas.0702254104
Publication status	Published - Jun 12 2007
Externally published	Yes

Keywords

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

ASJC Scopus subject areas

General

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10.1073/pnas.0702254104

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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. (2007). Bisphosphonates target multiple sites in both cis- and trans- prenyltransferases. Proceedings of the National Academy of Sciences of the United States of America, 104(24), 10022-10027. https://doi.org/10.1073/pnas.0702254104

Guo, RT, Cao, R, Liang, PH, Ko, TP, Chang, TH, Hudock, MP, Jeng, WY, 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

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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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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

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

Abstract

Keywords

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