Journal article
Meta-omic characterization of the marine invertebrate microbial consortium that produces the chemotherapeutic natural product ET-743
ACS chemical biology, v 6(11), pp 1244-1256
18 Nov 2011
PMID: 21875091
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
In many macroorganisms, the ultimate source of potent biologically active natural products has remained elusive due to an inability to identify and culture the producing symbiotic microorganisms. As a model system for developing a meta-omic approach to identify and characterize natural product pathways from invertebrate-derived microbial consortia we chose to investigate the ET-743 (Yondelis®) biosynthetic pathway. This molecule is an approved anti-cancer agent obtained in low abundance (10
−4
–10
−5
% w/w) from the tunicate
Ecteinascidia turbinata
, and is generated in suitable quantities for clinical use by a lengthy semi-synthetic process. Based on structural similarities to three bacterial secondary metabolites, we hypothesized that ET-743 is the product of a marine bacterial symbiont. Using metagenomic sequencing of total DNA from the tunicate/microbial consortium we targeted and assembled a 35 kb contig containing 25 genes that comprise the core of the NRPS biosynthetic pathway for this valuable anti-cancer agent. Rigorous sequence analysis based on codon usage of two large unlinked contigs suggests that
Candidatus Endoecteinascidia frumentensis
produces the ET-743 metabolite. Subsequent metaproteomic analysis confirmed expression of three key biosynthetic proteins. Moreover, the predicted activity of an enzyme for 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. We expect that the interdisciplinary approach described is applicable to diverse host-symbiont systems that generate valuable natural products for drug discovery and development.
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Details
- Title
- Meta-omic characterization of the marine invertebrate microbial consortium that produces the chemotherapeutic natural product ET-743
- Creators
- Christopher M Rath - Life Sciences Institute, University of Michigan, Ann Arbor, MIBenjamin Janto - Center for Genomic Sciences, Allegheny-Singer Research Institute, Allegheny General Hospital, Pittsburgh; PAJosh Earl - Center for Genomic Sciences, Allegheny-Singer Research Institute, Allegheny General Hospital, Pittsburgh; PAAzad Ahmed - Center for Genomic Sciences, Allegheny-Singer Research Institute, Allegheny General Hospital, Pittsburgh; PAFen Z Hu - Center for Genomic Sciences, Allegheny-Singer Research Institute, Allegheny General Hospital, Pittsburgh; PALuisa Hiller - Center for Genomic Sciences, Allegheny-Singer Research Institute, Allegheny General Hospital, Pittsburgh; PAMeg Dahlgren - Center for Genomic Sciences, Allegheny-Singer Research Institute, Allegheny General Hospital, Pittsburgh; PARachael Kreft - Center for Genomic Sciences, Allegheny-Singer Research Institute, Allegheny General Hospital, Pittsburgh; PAFengan Yu - Life Sciences Institute, University of Michigan, Ann Arbor, MIJeremy J Wolff - Bruker Daltonik, Billerica, MAHye Kyong Kweon - Department of Biological Chemistry, University of Michigan, Ann Arbor, MIMichael A Christiansen - Department of Chemistry, Colorado State University, Fort Collins, COKristina Håkansson - Department of Chemistry, University of Michigan, Ann Arbor, MIRobert M Williams - Department of Chemistry, Colorado State University, Fort Collins, COGarth D Ehrlich - Center for Genomic Sciences, Allegheny-Singer Research Institute, Allegheny General Hospital, Pittsburgh; PADavid H Sherman - Life Sciences Institute, University of Michigan, Ann Arbor, MI
- Publication Details
- ACS chemical biology, v 6(11), pp 1244-1256
- Publisher
- American Chemical Society; Washington, DC
- Grant note
- U01 TW007404-08 || TW / Fogarty International Center : FIC R01 CA070375-08 || CA / National Cancer Institute : NCI
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000297038800013
- Scopus ID
- 2-s2.0-81555208983
- Other Identifier
- 991014877902404721
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology