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Published on December 4, 2003; 10.1104/pp.103.029389

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Received July 1, 2003
Returned for revision August 27, 2003
Accepted September 21, 2003

Biosynthesis of Camptothecin. In Silico and in Vivo Tracer Study from [1-13C]Glucose

Yasuyo Yamazaki , Mariko Kitajima , Masanori Arita , Hiromitsu Takayama , Hiroshi Sudo , Mami Yamazaki , Norio Aimi , and Kazuki Saito *

Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan (Y.Y., M.K., H.T., H.S., M.Y., N.A., K.S.); and Computational Biology Research Center, National Institute of Advanced Industrial Science and Technology and Precursory Research for Embryonic Science and Technology, Japan Science and Technology Corporation, 2-41-6 Aomi, Koto-ku, Tokyo 135-0064, Japan (M.A.)

* Corresponding author; email: ksaito{at}p.chiba-u.ac.jp.

Camptothecin derivatives are clinically used antitumor alkaloids that belong to monoterpenoid indole alkaloids. In this study, we investigated the biosynthetic pathway of camptothecin from [1-13C]glucose (Glc) by in silico and in vivo studies. The in silico study measured the incorporation of Glc into alkaloids using the Atomic Reconstruction of Metabolism software and predicted the labeling patterns of successive metabolites from [1-13C]Glc. The in vivo study followed incorporation of [1-13C]Glc into camptothecin with hairy roots of Ophiorrhiza pumila by 13C nuclear magnetic resonance spectroscopy. The 13C-labeling pattern of camptothecin isolated from the hairy roots clearly showed that the monoterpene-secologanin moiety was synthesized via the 2C-methyl-D-erythritol 4-phosphate pathway, not via the mevalonate pathway. This conclusion was supported by differential inhibition of camptothecin accumulation by the pathway-specific inhibitors (fosmidomycin and lovastatin). The quinoline moiety from tryptophan was also labeled as predicted by the Atomic Reconstruction of Metabolism program via the shikimate pathway. These results indicate that camptothecin is formed by the combination of the 2C-methyl-D-erythritol 4-phosphate pathway and the shikimate pathway. This study provides the innovative example for how a computer-aided comprehensive metabolic analysis will refine the experimental design to obtain more precise biological information.




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