Bacterial biosynthesis and maturation of the didemnin anti-cancer agents
Kersten, Roland D.
Nam, Sang Jip
Al-Suwailem, Abdulaziz M.
Fenical, William H.
Dorrestein, Pieter C.
Moore, Bradley S.
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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.
SponsorsWe 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.).
PublisherAmerican Chemical Society (ACS)
PubMed Central IDPMC3401512
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