skip to main content
DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Identification and analysis of the bacterial endosymbiont specialized for production of the chemotherapeutic natural product ET-743

Abstract

Ecteinascidin 743 (ET-743, Yondelis) is a clinically approved chemotherapeutic natural product isolated from the Caribbean mangrove tunicate Ecteinascidia turbinata. Researchers have long suspected that a microorganism may be the true producer of the anti-cancer drug, but its genome has remained elusive due to our inability to culture the bacterium in the laboratory using standard techniques. Here, we sequenced and assembled the complete genome of the ET-743 producer, Candidatus Endoecteinascidia frumentensis, directly from metagenomic DNA isolated from the tunicate. Analysis of the ~631 kb microbial genome revealed strong evidence of an endosymbiotic lifestyle and extreme genome reduction. Phylogenetic analysis suggested that the producer of the anti-cancer drug is taxonomically distinct from other sequenced microorganisms and could represent a new family of Gammaproteobacteria. The complete genome has also greatly expanded our understanding of ET-743 production and revealed new biosynthetic genes dispersed across more than 173 kb of the small genome. The gene cluster’s architecture and its preservation demonstrate that the drug is likely essential to the interactions of the microorganism with its mangrove tunicate host. In conclusion, taken together, these studies elucidate the lifestyle of a unique, and pharmaceutically-important microorganism and highlight the wide diversity of bacteria capable of making potent naturalmore » products.« less

Authors:
 [1];  [1];  [1];  [1];  [1]
  1. Univ. of Michigan, Ann Arbor, MI (United States)
Publication Date:
Research Org.:
Univ. of Michigan, Ann Arbor, MI (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1344906
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Accepted Manuscript
Journal Name:
Environmental Microbiology
Additional Journal Information:
Journal Volume: 17; Journal Issue: 10; Journal ID: ISSN 1462-2912
Publisher:
Wiley
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 54 ENVIRONMENTAL SCIENCES

Citation Formats

Schofield, Michael M., Jain, Sunit, Porat, Daphne, Dick, Gregory J., and Sherman, David H. Identification and analysis of the bacterial endosymbiont specialized for production of the chemotherapeutic natural product ET-743. United States: N. p., 2015. Web. doi:10.1111/1462-2920.12908.
Schofield, Michael M., Jain, Sunit, Porat, Daphne, Dick, Gregory J., & Sherman, David H. Identification and analysis of the bacterial endosymbiont specialized for production of the chemotherapeutic natural product ET-743. United States. doi:10.1111/1462-2920.12908.
Schofield, Michael M., Jain, Sunit, Porat, Daphne, Dick, Gregory J., and Sherman, David H. Tue . "Identification and analysis of the bacterial endosymbiont specialized for production of the chemotherapeutic natural product ET-743". United States. doi:10.1111/1462-2920.12908. https://www.osti.gov/servlets/purl/1344906.
@article{osti_1344906,
title = {Identification and analysis of the bacterial endosymbiont specialized for production of the chemotherapeutic natural product ET-743},
author = {Schofield, Michael M. and Jain, Sunit and Porat, Daphne and Dick, Gregory J. and Sherman, David H.},
abstractNote = {Ecteinascidin 743 (ET-743, Yondelis) is a clinically approved chemotherapeutic natural product isolated from the Caribbean mangrove tunicate Ecteinascidia turbinata. Researchers have long suspected that a microorganism may be the true producer of the anti-cancer drug, but its genome has remained elusive due to our inability to culture the bacterium in the laboratory using standard techniques. Here, we sequenced and assembled the complete genome of the ET-743 producer, Candidatus Endoecteinascidia frumentensis, directly from metagenomic DNA isolated from the tunicate. Analysis of the ~631 kb microbial genome revealed strong evidence of an endosymbiotic lifestyle and extreme genome reduction. Phylogenetic analysis suggested that the producer of the anti-cancer drug is taxonomically distinct from other sequenced microorganisms and could represent a new family of Gammaproteobacteria. The complete genome has also greatly expanded our understanding of ET-743 production and revealed new biosynthetic genes dispersed across more than 173 kb of the small genome. The gene cluster’s architecture and its preservation demonstrate that the drug is likely essential to the interactions of the microorganism with its mangrove tunicate host. In conclusion, taken together, these studies elucidate the lifestyle of a unique, and pharmaceutically-important microorganism and highlight the wide diversity of bacteria capable of making potent natural products.},
doi = {10.1111/1462-2920.12908},
journal = {Environmental Microbiology},
number = 10,
volume = 17,
place = {United States},
year = {2015},
month = {7}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record

Citation Metrics:
Cited by: 25 works
Citation information provided by
Web of Science

Save / Share:

Works referenced in this record:

antiSMASH 2.0—a versatile platform for genome mining of secondary metabolite producers
journal, May 2013

  • Blin, Kai; Medema, Marnix H.; Kazempour, Daniyal
  • Nucleic Acids Research, Vol. 41, Issue W1
  • DOI: 10.1093/nar/gkt449

Production of Ecteinascidia turbinata (Ascidiacea: Perophoridae) for Obtaining Anticancer Compounds
journal, December 2000


Toward Automatic Reconstruction of a Highly Resolved Tree of Life
journal, March 2006


Enantioselective Total Synthesis of Ecteinascidin 743
journal, January 1996

  • Corey, E. J.; Gin, David Y.; Kania, Robert S.
  • Journal of the American Chemical Society, Vol. 118, Issue 38
  • DOI: 10.1021/ja962480t

Development of Yondelis® (trabectedin, ET-743). A semisynthetic process solves the supply problem
journal, January 2009

  • Cuevas, Carmen; Francesch, Andrés
  • Natural Product Reports, Vol. 26, Issue 3
  • DOI: 10.1039/b808331m

Community-wide analysis of microbial genome sequence signatures
journal, January 2009

  • Dick, Gregory J.; Andersson, Anders F.; Baker, Brett J.
  • Genome Biology, Vol. 10, Issue 8
  • DOI: 10.1186/gb-2009-10-8-r85

BAGEL3: automated identification of genes encoding bacteriocins and (non-)bactericidal posttranslationally modified peptides
journal, May 2013

  • van Heel, Auke J.; de Jong, Anne; Montalbán-López, Manuel
  • Nucleic Acids Research, Vol. 41, Issue W1
  • DOI: 10.1093/nar/gkt391

Core Assembly Mechanism of Quinocarcin/SF-1739: Bimodular Complex Nonribosomal Peptide Synthetases for Sequential Mannich-type Reactions
journal, December 2013


Endosymbiotic Bacteria in Insects: Their Diversity and Culturability
journal, January 2009


Towards a Genome-Based Taxonomy for Prokaryotes
journal, September 2005


Circos: An information aesthetic for comparative genomics
journal, June 2009


Deletional Bias across the Three Domains of Life
journal, January 2009

  • Kuo, Chih-Horng; Ochman, Howard
  • Genome Biology and Evolution, Vol. 1
  • DOI: 10.1093/gbe/evp016

The consequences of genetic drift for bacterial genome complexity
journal, June 2009


Bacterial Endosymbiosis in a Chordate Host: Long-Term Co-Evolution and Conservation of Secondary Metabolism
journal, December 2013


Genome streamlining and chemical defense in a coral reef symbiosis
journal, November 2012

  • Kwan, J. C.; Donia, M. S.; Han, A. W.
  • Proceedings of the National Academy of Sciences, Vol. 109, Issue 50
  • DOI: 10.1073/pnas.1213820109

Host Control of Symbiont Natural Product Chemistry in Cryptic Populations of the Tunicate Lissoclinum patella
journal, May 2014


Evolution of an endofungal Lifestyle: Deductions from the Burkholderia rhizoxinica Genome
journal, May 2011

  • Lackner, Gerald; Moebius, Nadine; Partida-Martinez, Laila P.
  • BMC Genomics, Vol. 12, Issue 1
  • DOI: 10.1186/1471-2164-12-210

Automated genome mining for natural products
journal, January 2009


Ecteinascidia turbinata Extracts Inhibit DNA Synthesis in Lymphocytes After Mitogenic Stimulation by Lectins
journal, November 1975


Defense of Ascidians and Their Conspicuous Larvae: Adult vs. Larval Chemical Defenses
journal, February 1992

  • Lindquist, Niels; Hay, Mark E.; Fenical, William
  • Ecological Monographs, Vol. 62, Issue 4
  • DOI: 10.2307/2937316

Extreme genome reduction in symbiotic bacteria
journal, November 2011

  • McCutcheon, John P.; Moran, Nancy A.
  • Nature Reviews Microbiology, Vol. 10, Issue 1
  • DOI: 10.1038/nrmicro2670

IMG/M 4 version of the integrated metagenome comparative analysis system
journal, October 2013

  • Markowitz, Victor M.; Chen, I-Min A.; Chu, Ken
  • Nucleic Acids Research, Vol. 42, Issue D1, p. D568-D573
  • DOI: 10.1093/nar/gkt919

IMG 4 version of the integrated microbial genomes comparative analysis system
journal, October 2013

  • Markowitz, Victor M.; Chen, I-Min A.; Palaniappan, Krishna
  • Nucleic Acids Research, Vol. 42, Issue D1
  • DOI: 10.1093/nar/gkt963

Accelerated evolution and Muller's rachet in endosymbiotic bacteria.
journal, April 1996


Genomics and Evolution of Heritable Bacterial Symbionts
journal, December 2008


Carbon metabolism of intracellular bacteria
journal, January 2006


Defensive Bacteriome Symbiont with a Drastically Reduced Genome
journal, August 2013


Natural Products As Sources of New Drugs over the 30 Years from 1981 to 2010
journal, January 2012

  • Newman, David J.; Cragg, Gordon M.
  • Journal of Natural Products, Vol. 75, Issue 3
  • DOI: 10.1021/np200906s

Host cell-free growth of the Q fever bacterium Coxiella burnetii
journal, February 2009

  • Omsland, A.; Cockrell, D. C.; Howe, D.
  • Proceedings of the National Academy of Sciences, Vol. 106, Issue 11
  • DOI: 10.1073/pnas.0812074106

The Pyruvate Dehydrogenase Complexes: Structure-based Function and Regulation
journal, May 2014

  • Patel, Mulchand S.; Nemeria, Natalia S.; Furey, William
  • Journal of Biological Chemistry, Vol. 289, Issue 24
  • DOI: 10.1074/jbc.R114.563148

A Small Microbial Genome: The End of a Long Symbiotic Relationship?
journal, October 2006


Bacterial diversity associated with the Caribbean tunicate Ecteinascidia turbinata
journal, January 2007

  • Pérez-Matos, Ana E.; Rosado, William; Govind, Nadathur S.
  • Antonie van Leeuwenhoek, Vol. 92, Issue 2
  • DOI: 10.1007/s10482-007-9143-9

Hijacking a hydroxyethyl unit from a central metabolic ketose into a nonribosomal peptide assembly line
journal, May 2012

  • Peng, C.; Pu, J. -Y.; Song, L. -Q.
  • Proceedings of the National Academy of Sciences, Vol. 109, Issue 22
  • DOI: 10.1073/pnas.1204232109

Metabolites from symbiotic bacteria
journal, January 2009


A new Myxococcus xanthus gene cluster for the biosynthesis of the antibiotic saframycin Mx1 encoding a peptide synthetase
journal, August 1995


Operon formation is driven by co-regulation and not by horizontal gene transfer
journal, May 2005


Meta-omic Characterization of the Marine Invertebrate Microbial Consortium That Produces the Chemotherapeutic Natural Product ET-743
journal, September 2011

  • Rath, Christopher M.; Janto, Benjamin; Earl, Josh
  • ACS Chemical Biology, Vol. 6, Issue 11
  • DOI: 10.1021/cb200244t

Ecteinascidins 729, 743, 745, 759A, 759B, and 770: potent antitumor agents from the Caribbean tunicate Ecteinascidia turbinata
journal, July 1990

  • Rinehart, Kenneth L.; Holt, Tom G.; Fregeau, Nancy L.
  • The Journal of Organic Chemistry, Vol. 55, Issue 15
  • DOI: 10.1021/jo00302a007

Genome sequence of the endocellular bacterial symbiont of aphids Buchnera sp. APS
journal, September 2000

  • Shigenobu, Shuji; Watanabe, Hidemi; Hattori, Masahira
  • Nature, Vol. 407, Issue 6800
  • DOI: 10.1038/35024074

Measurement of in Situ Activities of Nonphotosynthetic Microorganisms in Aquatic and Terrestrial Habitats
journal, October 1985


On the evolution of functional secondary metabolites (natural products)
journal, January 1992


Horizontal Gene Transfer and the Evolution of Secondary Metabolite Gene Clusters in Fungi: An Hypothesis
journal, August 2000


CLUSEAN: A computer-based framework for the automated analysis of bacterial secondary metabolite biosynthetic gene clusters
journal, March 2009


Genome evolution in bacterial endosymbionts of insects
journal, November 2002

  • Wernegreen, Jennifer J.
  • Nature Reviews Genetics, Vol. 3, Issue 11
  • DOI: 10.1038/nrg931

Why Are Secondary Metabolites (Natural Products) Biosynthesized?
journal, November 1989

  • Williams, Dudley H.; Stone, Martin J.; Hauck, Peter R.
  • Journal of Natural Products, Vol. 52, Issue 6
  • DOI: 10.1021/np50066a001

Metabolic Complementarity and Genomics of the Dual Bacterial Symbiosis of Sharpshooters
journal, June 2006


Uniting the classification of cultured and uncultured bacteria and archaea using 16S rRNA gene sequences
journal, August 2014

  • Yarza, Pablo; Yilmaz, Pelin; Pruesse, Elmar
  • Nature Reviews Microbiology, Vol. 12, Issue 9
  • DOI: 10.1038/nrmicro3330

Chemical defense and aposematic coloration in larvae of the ascidian Ecteinascidia turbinata
journal, December 1987


    Works referencing / citing this record:

    Strategies to diversify natural products for drug discovery
    journal, October 2017

    • Li, Gang; Lou, Hong-Xiang
    • Medicinal Research Reviews, Vol. 38, Issue 4
    • DOI: 10.1002/med.21474