1. Structure and Inhibition of Tuberculosinol Synthase and Decaprenyl Diphosphate Synthase from Mycobacterium tuberculosis
- Author
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Chun-Hsiang Huang, Tsutomu Hoshino, Andrew H.-J. Wang, Wenting Liu, Tzu-Ping Ko, Dean C. Crick, Rey-Ting Guo, Eric Oldfield, Po-Huang Liang, Hsiu Chien Chan, Lilan Zhang, Xinxin Feng, Yingying Zheng, Shannon Bogue, Chiaki Nakano, Pin Lv, and Yumei Hu
- Subjects
Models, Molecular ,Protein Conformation ,Phosphatase ,Virulence ,01 natural sciences ,Biochemistry ,Catalysis ,Virulence factor ,Article ,Mycobacterium tuberculosis ,03 medical and health sciences ,Colloid and Surface Chemistry ,Protein structure ,medicine ,Transferase ,Enzyme Inhibitors ,030304 developmental biology ,0303 health sciences ,Alkyl and Aryl Transferases ,biology ,ATP synthase ,Diphosphonates ,010405 organic chemistry ,Chemistry ,General Chemistry ,biology.organism_classification ,0104 chemical sciences ,3. Good health ,Mechanism of action ,biology.protein ,Mutagenesis, Site-Directed ,medicine.symptom ,Diterpenes - 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.
- Published
- 2014