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    Bacterial biosynthesis and maturation of the didemnin anti-cancer agents

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    Name:
    Bacterial biosynthesis.pdf
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    2.237Mb
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    PDF
    Description:
    Accepted manuscript
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    Type
    Article
    Authors
    Xü, Ying
    Kersten, Roland D.
    Nam, Sang Jip
    Lu, Liang
    Al-Suwailem, Abdulaziz M.
    Zheng, Huajun
    Fenical, William H.
    Dorrestein, Pieter C.
    Moore, Bradley S.
    Qian, Pei-Yuan cc
    KAUST Department
    Coastal and Marine Resources Core Lab
    Red Sea Research Center (RSRC)
    Date
    2012-03-29
    Online Publication Date
    2012-04-06
    Print Publication Date
    2012-05-23
    Embargo End Date
    2013-03-29
    Permanent link to this record
    http://hdl.handle.net/10754/562193
    
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    Abstract
    The anti-neoplastic agent didemnin B from the Caribbean tunicate Trididemnum solidum was the first marine drug to be clinically tested in humans. Because of its limited supply and its complex cyclic depsipeptide structure, considerable challenges were encountered during didemnin B's development that continue to limit aplidine (dehydrodidemnin B), which is currently being evaluated in numerous clinical trials. Herein we show that the didemnins are bacterial products produced by the marine α-proteobacteria Tistrella mobilis and Tistrella bauzanensis via a unique post-assembly line maturation process. Complete genome sequence analysis of the 6,513,401 bp T. mobilis strain KA081020-065 with its five circular replicons revealed the putative didemnin biosynthetic gene cluster (did) on the 1,126,962 bp megaplasmid pTM3. The did locus encodes a 13-module hybrid non-ribosomal peptide synthetase-polyketide synthase enzyme complex organized in a collinear arrangement for the synthesis of the fatty acylglutamine ester derivatives didemnins X and Y rather than didemnin B as first anticipated. Imaging mass spectrometry of T. mobilis bacterial colonies captured the time-dependent extracellular conversion of the didemnin X and Y precursors to didemnin B, in support of an unusual post-synthetase activation mechanism. Significantly, the discovery of the didemnin biosynthetic gene cluster may provide a long-term solution to the supply problem that presently hinders this group of marine natural products and pave the way for the genetic engineering of new didemnin congeners. © 2012 American Chemical Society.
    Sponsors
    We thank Z. Shao for providing the Pacific Ocean Tistrella strains and N. Ziemert, J. Yang and P. Lai for assistance with data analysis. Financial support was provided by King Abdullah University of Science and Technology (SA-C0040/UK-C0016 to P.Y.Q.), China Ocean Mineral Resources Research and Development Association (DY125-15-T-02 to P.Y.Q), and the National Institutes of Health (GM085770 to B.S.M., CA044848 to W.F., GM086283 and S10RR029121 to P.C.D.).
    Publisher
    American Chemical Society (ACS)
    Journal
    Journal of the American Chemical Society
    DOI
    10.1021/ja301735a
    PubMed ID
    22458477
    PubMed Central ID
    PMC3401512
    Additional Links
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3401512
    http://europepmc.org/articles/pmc3401512?pdf=render
    ae974a485f413a2113503eed53cd6c53
    10.1021/ja301735a
    Scopus Count
    Collections
    Articles; Red Sea Research Center (RSRC); Coastal and Marine Resources Core Lab

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