Bacterial biosynthesis and maturation of the didemnin anti-cancer agents

Handle URI:
http://hdl.handle.net/10754/562193
Title:
Bacterial biosynthesis and maturation of the didemnin anti-cancer agents
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, Peiyuan
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.
KAUST Department:
Coastal and Marine Resources Core Lab; Red Sea Research Center (RSRC)
Publisher:
American Chemical Society
Journal:
Journal of the American Chemical Society
Issue Date:
23-May-2012
DOI:
10.1021/ja301735a
PubMed ID:
22458477
PubMed Central ID:
PMC3401512
Type:
Article
ISSN:
00027863
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.).
Additional Links:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3401512
Appears in Collections:
Articles; Red Sea Research Center (RSRC); Coastal and Marine Resources Core Lab

Full metadata record

DC FieldValue Language
dc.contributor.authorXü, Yingen
dc.contributor.authorKersten, Roland D.en
dc.contributor.authorNam, Sang Jipen
dc.contributor.authorLu, Liangen
dc.contributor.authorAl-Suwailem, Abdulaziz M.en
dc.contributor.authorZheng, Huajunen
dc.contributor.authorFenical, William H.en
dc.contributor.authorDorrestein, Pieter C.en
dc.contributor.authorMoore, Bradley S.en
dc.contributor.authorQian, Peiyuanen
dc.date.accessioned2015-08-03T09:46:57Zen
dc.date.available2015-08-03T09:46:57Zen
dc.date.issued2012-05-23en
dc.identifier.issn00027863en
dc.identifier.pmid22458477en
dc.identifier.doi10.1021/ja301735aen
dc.identifier.urihttp://hdl.handle.net/10754/562193en
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.en
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.).en
dc.publisherAmerican Chemical Societyen
dc.relation.urlhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3401512en
dc.titleBacterial biosynthesis and maturation of the didemnin anti-cancer agentsen
dc.typeArticleen
dc.contributor.departmentCoastal and Marine Resources Core Laben
dc.contributor.departmentRed Sea Research Center (RSRC)en
dc.identifier.journalJournal of the American Chemical Societyen
dc.identifier.pmcidPMC3401512en
dc.contributor.institutionDivision of Life Science, School of Science, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, Hong Kongen
dc.contributor.institutionCenter for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California at San Diego, San Diego, CA 92093, United Statesen
dc.contributor.institutionShanghai-MOST Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai, 250 Bi Bo Road, Shanghai 201203, Chinaen
dc.contributor.institutionSkaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, San Diego, CA 92093, United Statesen
dc.contributor.institutionCollege of Pharmacy, Sunchon National University, Suncheon 540-950, South Koreaen
kaust.authorAl-Suwailem, Abdulaziz M.en

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