In many macroorganisms, access to biologically active natural products has not been possible due to an inability to identify and culture producing microorganisms. We developed a meta-omic approach to identify and characterize the ET-743 (Yondelis�) biosynthetic pathway. This approved anti-cancer drug is obtained from the tunicate Ecteinascidia turbinata, and clinically supplied by a lengthy semi-synthetic process. Using metagenomic sequencing of total DNA from the tunicate/microbial consortium we assembled the core biosynthetic pathway from the producing bacteria Candidatus Endoecteinascidia frumentensis. Metaproteomics analysis confirmed expression of biosynthetic proteins and the activity of a key enzyme involved in assembly of the tetrahydroisoquinoline core of ET-743 was verified in vitro. This work provides a foundation for direct production of the drug and new analogs through metabolic engineering in an amenable host. We expect that this interdisciplinary approach is applicable to diverse host-symbiont systems that generate valuable natural products for drug discovery and development.

Meta-omic characterization of the marine invertebrate microbial consortium that produces the chemotherapeutic natural product ET-743

243rd National Meeting (2012)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.