Solution of the multistep pathway for assembly of corynanthean, strychnos, iboga, and aspidosperma monoterpenoid indole alkaloids from 19E-geissoschizine

Significance The multistep assembly of catharanthine and tabersonine from strictosidine remains poorly characterized for understanding the biochemistry of anticancer monoterpenoid indole alkaloid (MIA) biosynthesis in the medicinal plant, Catharanthus roseus. The seven-step pathway from 19E-geissoschizine to four major MIA skeletons enables the assembly of catharanthine and tabersonine that complete the pathway for biosynthesis of the anticancer drugs, anhydrovinblastine and vincristine as well as for production of other biologically active MIAs. Monoterpenoid indole alkaloids (MIAs) possess a diversity of alkaloid skeletons whose biosynthesis is poorly understood. A bioinformatic search of candidate genes, combined with their virus-induced gene silencing, targeted MIA profiling and in vitro/in vivo pathway reconstitution identified and functionally characterized six genes as well as a seventh enzyme reaction required for the conversion of 19E-geissoschizine to tabersonine and catharanthine. The involvement of pathway intermediates in the formation of four MIA skeletons is described, and the role of stemmadenine-O-acetylation in providing necessary reactive substrates for the formation of iboga and aspidosperma MIAs is described. The results enable the assembly of complex dimeric MIAs used in cancer chemotherapy and open the way to production of many other biologically active MIAs that are not easily available from nature.

• Publication year

  2018

• Venue

  Proceedings of the National Academy of Sciences of the United States of America

• Publication date

  2018-03-06

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1073/pnas.1719979115PMID 29511102PMCID 5866588
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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