Structure and inhibition of tuberculosinol synthase and decaprenyl diphosphate synthase from mycobacterium tuberculosis

Hsiu Chien Chan; Xinxin Feng; Tzu Ping Ko; Chun Hsiang Huang; Yumei Hu; Yingying Zheng; Shannon Bogue; Chiaki Nakano; Tsutomu Hoshino; Lilan Zhang; Pin Lv; Wenting Liu; Dean C. Crick; Po Huang Liang; Andrew H.J. Wang; Eric Oldfield; Rey Ting Guo

doi:10.1021/ja413127v

Structure and inhibition of tuberculosinol synthase and decaprenyl diphosphate synthase from mycobacterium tuberculosis

Hsiu Chien Chan, Xinxin Feng, Tzu Ping Ko, Chun Hsiang Huang, Yumei Hu, Yingying Zheng, Shannon Bogue, Chiaki Nakano, Tsutomu Hoshino, Lilan Zhang, Pin Lv, Wenting Liu, Dean C. Crick, Po Huang Liang, Andrew H.J. Wang, Eric Oldfield, Rey Ting Guo

Research output: Contribution to journal › Article › peer-review

36 Citations (Scopus)

Abstract

We have obtained the structure of the bacterial diterpene synthase, tuberculosinol/iso-tuberculosinol synthase (Rv3378c) from Mycobacterium tuberculosis, a target for anti-infective therapies that block virulence factor formation. This phosphatase adopts the same fold as found in the Z- or cis-prenyltransferases. We also obtained structures containing the tuberculosinyl diphosphate substrate together with one bisphosphonate inhibitor-bound structure. These structures together with the results of site-directed mutagenesis suggest an unusual mechanism of action involving two Tyr residues. Given the similarity in local and global structure between Rv3378c and the M. tuberculosis cis-decaprenyl diphosphate synthase (DPPS; Rv2361c), the possibility exists for the development of inhibitors that target not only virulence but also cell wall biosynthesis, based in part on the structures reported here.

Original language	English
Pages (from-to)	2892-2896
Number of pages	5
Journal	Journal of the American Chemical Society
Volume	136
Issue number	7
DOIs	https://doi.org/10.1021/ja413127v
Publication status	Published - Feb 19 2014
Externally published	Yes

ASJC Scopus subject areas

Catalysis
General Chemistry
Biochemistry
Colloid and Surface Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1021/ja413127v

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Chan, H. C., Feng, X., Ko, T. P., Huang, C. H., Hu, Y., Zheng, Y., Bogue, S., Nakano, C., Hoshino, T., Zhang, L., Lv, P., Liu, W., Crick, D. C., Liang, P. H., Wang, A. H. J., Oldfield, E., & Guo, R. T. (2014). Structure and inhibition of tuberculosinol synthase and decaprenyl diphosphate synthase from mycobacterium tuberculosis. Journal of the American Chemical Society, 136(7), 2892-2896. https://doi.org/10.1021/ja413127v

Chan, HC, Feng, X, Ko, TP, Huang, CH, Hu, Y, Zheng, Y, Bogue, S, Nakano, C, Hoshino, T, Zhang, L, Lv, P, Liu, W, Crick, DC, Liang, PH, Wang, AHJ, Oldfield, E & Guo, RT 2014, 'Structure and inhibition of tuberculosinol synthase and decaprenyl diphosphate synthase from mycobacterium tuberculosis', Journal of the American Chemical Society, vol. 136, no. 7, pp. 2892-2896. https://doi.org/10.1021/ja413127v

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title = "Structure and inhibition of tuberculosinol synthase and decaprenyl diphosphate synthase from mycobacterium tuberculosis",

abstract = "We have obtained the structure of the bacterial diterpene synthase, tuberculosinol/iso-tuberculosinol synthase (Rv3378c) from Mycobacterium tuberculosis, a target for anti-infective therapies that block virulence factor formation. This phosphatase adopts the same fold as found in the Z- or cis-prenyltransferases. We also obtained structures containing the tuberculosinyl diphosphate substrate together with one bisphosphonate inhibitor-bound structure. These structures together with the results of site-directed mutagenesis suggest an unusual mechanism of action involving two Tyr residues. Given the similarity in local and global structure between Rv3378c and the M. tuberculosis cis-decaprenyl diphosphate synthase (DPPS; Rv2361c), the possibility exists for the development of inhibitors that target not only virulence but also cell wall biosynthesis, based in part on the structures reported here.",

author = "Chan, {Hsiu Chien} and Xinxin Feng and Ko, {Tzu Ping} and Huang, {Chun Hsiang} and Yumei Hu and Yingying Zheng and Shannon Bogue and Chiaki Nakano and Tsutomu Hoshino and Lilan Zhang and Pin Lv and Wenting Liu and Crick, {Dean C.} and Liang, {Po Huang} and Wang, {Andrew H.J.} and Eric Oldfield and Guo, {Rey Ting}",

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doi = "10.1021/ja413127v",

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AU - Chan, Hsiu Chien

AU - Feng, Xinxin

AU - Ko, Tzu Ping

AU - Huang, Chun Hsiang

AU - Hu, Yumei

AU - Zheng, Yingying

AU - Bogue, Shannon

AU - Nakano, Chiaki

AU - Hoshino, Tsutomu

AU - Zhang, Lilan

AU - Lv, Pin

AU - Liu, Wenting

AU - Crick, Dean C.

AU - Liang, Po Huang

AU - Wang, Andrew H.J.

AU - Oldfield, Eric

AU - Guo, Rey Ting

PY - 2014/2/19

Y1 - 2014/2/19

N2 - We have obtained the structure of the bacterial diterpene synthase, tuberculosinol/iso-tuberculosinol synthase (Rv3378c) from Mycobacterium tuberculosis, a target for anti-infective therapies that block virulence factor formation. This phosphatase adopts the same fold as found in the Z- or cis-prenyltransferases. We also obtained structures containing the tuberculosinyl diphosphate substrate together with one bisphosphonate inhibitor-bound structure. These structures together with the results of site-directed mutagenesis suggest an unusual mechanism of action involving two Tyr residues. Given the similarity in local and global structure between Rv3378c and the M. tuberculosis cis-decaprenyl diphosphate synthase (DPPS; Rv2361c), the possibility exists for the development of inhibitors that target not only virulence but also cell wall biosynthesis, based in part on the structures reported here.

AB - We have obtained the structure of the bacterial diterpene synthase, tuberculosinol/iso-tuberculosinol synthase (Rv3378c) from Mycobacterium tuberculosis, a target for anti-infective therapies that block virulence factor formation. This phosphatase adopts the same fold as found in the Z- or cis-prenyltransferases. We also obtained structures containing the tuberculosinyl diphosphate substrate together with one bisphosphonate inhibitor-bound structure. These structures together with the results of site-directed mutagenesis suggest an unusual mechanism of action involving two Tyr residues. Given the similarity in local and global structure between Rv3378c and the M. tuberculosis cis-decaprenyl diphosphate synthase (DPPS; Rv2361c), the possibility exists for the development of inhibitors that target not only virulence but also cell wall biosynthesis, based in part on the structures reported here.

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Structure and inhibition of tuberculosinol synthase and decaprenyl diphosphate synthase from mycobacterium tuberculosis

Abstract

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UN SDGs

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