Structure and inhibition of tuberculosinol synthase and decaprenyl diphosphate synthase from Mycobacterium tuberculosis.
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.
Industrial Enzymes National Engineering Laboratory, Tianjin Institute of Industrial Biotechnology , Tianjin 300308, China.
Hsiu-Chien
HC
Chan
Xinxin
X
Feng
Tzu-Ping
TP
Ko
Chun-Hsiang
CH
Huang
Yumei
Y
Hu
Yingying
Y
Zheng
Shannon
S
Bogue
Chiaki
C
Nakano
Tsutomu
T
Hoshino
Lilan
L
Zhang
Pin
P
Lv
Wenting
W
Liu
Dean C
DC
Crick
Po-Huang
PH
Liang
Andrew H-J
AH
Wang
Eric
E
Oldfield
Rey-Ting
RT
Guo
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D004164:Diphosphonates / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004224:Diterpenes / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D011487:Protein Conformation
D004164:Diphosphonates; D004224:Diterpenes; D004791:Enzyme Inhibitors; C551415:tuberculosinol; D019883:Alkyl and Aryl Transferases; C039821:decaprenyl pyrophosphate synthetase