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 journalArticlepeer-review

31 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 languageEnglish
Pages (from-to)2892-2896
Number of pages5
JournalJournal of the American Chemical Society
Volume136
Issue number7
DOIs
Publication statusPublished - Feb 19 2014
Externally publishedYes

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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