Scaffold tailoring by a newly detected Pictet-Spenglerase activity of strictosidine synthase: from the common tryptoline skeleton to the rare piperazino-indole framework.
The Pictet-Spenglerase strictosidine synthase (STR1) has been recognized as a key enzyme in the biosynthesis of some 2000 indole alkaloids in plants, some with high therapeutic value. In this study, a novel function of STR1 has been detected which allows for the first time a simple enzymatic synthesis of the strictosidine analogue 3 harboring the piperazino[1,2-a]indole (PI) scaffold and to switch from the common tryptoline (hydrogenated carboline) to the rare PI skeleton. Insight into the reaction is provided by X-ray crystal analysis and modeling of STR1 ligand complexes. STR1 presently provides exclusively access to 3 and can act as a source to generate by chemoenzymatic approaches libraries of this novel class of alkaloids which may have new biological activities. Synthetic or natural monoterpenoid alkaloids with the PI core have not been reported before.
Institute of Materia Medica, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Fangrui
F
Wu
Huajian
H
Zhu
Lianli
L
Sun
Chitra
C
Rajendran
Meitian
M
Wang
Xin
X
Ren
Santosh
S
Panjikar
Artem
A
Cherkasov
Hongbin
H
Zou
Joachim
J
Stöckigt
D002243:Carbolines / Q000737:chemistry / Q000378:metabolism*; D019759:Carbon-Nitrogen Lyases / Q000378:metabolism*; D018360:Crystallography, X-Ray; D007211:Indoles / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism*; D011926:Rauwolfia / Q000737:chemistry / Q000201:enzymology*; D011994:Recombinant Proteins / Q000378:metabolism; D013379:Substrate Specificity
D002243:Carbolines; D007211:Indoles; D010879:Piperazines; D011994:Recombinant Proteins; C009804:tryptoline; D019759:Carbon-Nitrogen Lyases; C022684:strictosidine synthetase