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dc.contributor.authorXü, Ying
dc.contributor.authorKersten, Roland D.
dc.contributor.authorNam, Sang Jip
dc.contributor.authorLu, Liang
dc.contributor.authorAl-Suwailem, Abdulaziz M.
dc.contributor.authorZheng, Huajun
dc.contributor.authorFenical, William H.
dc.contributor.authorDorrestein, Pieter C.
dc.contributor.authorMoore, Bradley S.
dc.contributor.authorQian, Pei-Yuan
dc.date.accessioned2015-08-03T09:46:57Z
dc.date.available2015-08-03T09:46:57Z
dc.date.issued2012-03-29
dc.identifier.citationXu, Y., Kersten, R. D., Nam, S.-J., Lu, L., Al-Suwailem, A. M., Zheng, H., … Qian, P.-Y. (2012). Bacterial Biosynthesis and Maturation of the Didemnin Anti-cancer Agents. Journal of the American Chemical Society, 134(20), 8625–8632. doi:10.1021/ja301735a
dc.identifier.issn00027863
dc.identifier.pmid22458477
dc.identifier.doi10.1021/ja301735a
dc.identifier.urihttp://hdl.handle.net/10754/562193
dc.description.abstractThe 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.
dc.description.sponsorshipWe 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.).
dc.publisherAmerican Chemical Society (ACS)
dc.relation.urlhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3401512
dc.relation.urlhttp://europepmc.org/articles/pmc3401512?pdf=render
dc.rightsThis document is the Accepted Manuscript version of a Published Work that appeared in final form in [JournalTitle], copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see [ArticleLink].
dc.rightsThis file is an open access version redistributed from: http://europepmc.org/articles/pmc3401512?pdf=render
dc.titleBacterial biosynthesis and maturation of the didemnin anti-cancer agents
dc.typeArticle
dc.contributor.departmentCoastal and Marine Resources Core Lab
dc.contributor.departmentRed Sea Research Center (RSRC)
dc.identifier.journalJournal of the American Chemical Society
dc.identifier.pmcidPMC3401512
dc.rights.embargodate2013-03-29
dc.eprint.versionPost-print
dc.contributor.institutionDivision of Life Science, School of Science, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, Hong Kong
dc.contributor.institutionCenter for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California at San Diego, San Diego, CA 92093, United States
dc.contributor.institutionShanghai-MOST Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai, 250 Bi Bo Road, Shanghai 201203, China
dc.contributor.institutionSkaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, San Diego, CA 92093, United States
dc.contributor.institutionCollege of Pharmacy, Sunchon National University, Suncheon 540-950, South Korea
kaust.personAl-Suwailem, Abdulaziz M.
refterms.dateFOA2020-04-30T11:52:14Z
dc.date.published-online2012-04-06
dc.date.published-print2012-05-23


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