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Chubatsu Nunes, Helena Hitomi

University of British Columbia

Camptothecin (CPT) is a monoterpene indole alkaloid extracted from the native Chinese tree Camptotheca acuminata, commonly known as Happy Tree. Since its discovery in 1958, CPT has been derivatized to produce the widely used DNA topoisomerase I inhibitors and anticancer drugs Topotecan and Irinotecan. The low natural abundance of camptothecin and complex chemical structure challenge synthetic routes and hinder green production strategies that attempt to obtain this essential pharmaceutical. Therefore, the elucidation of its biosynthetic pathway will pave the way for sustainable alternatives to access CPT’s medical properties. This thesis focused on the investigation of two biosynthetic steps: the formation of CPT’s main intermediate, strictosidinic acid, as well as the enzymatic rearrangement of the indole moiety in the intermediate strictosamide. Strictosidine synthases from C. acuminata were able to condense secologanin and tryptamine to form the ester-based compound strictosidine, challenging the putative CPT pathway currently based on carboxylic acid intermediates. Furthermore, C. acuminata dioxygenase was identified as able to convert strictosamide into putative oxidized forms. Overall, this thesis is a step forward in the understanding of CPT biosynthesis and sets the stage for future gene discovery opportunities to promote a more sustainable and economic production of CPT and clinically-relevant derivatives.

Text

2024-11-23

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/86760

Biochemistry and Molecular Biology

University of British Columbia

UBCO

http://creativecommons.org/licenses/by-nc-nd/4.0/