Structure and Inhibition of Tuberculosinol Synthase and Decaprenyl Diphosphate Synthase from Mycobacterium tuberculosis

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• 作者：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
• 刊名：Journal of the American Chemical Society
• 出版年：2014
• 出版时间：February 19, 2014
• 年：2014
• 卷：136
• 期：7
• 页码：2892-2896
• 全文大小：390K
• ISSN：1520-5126

文摘

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.