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

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

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., 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.. 2015. "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}
}