Biosynthetic multitasking facilitates thalassospiramide structural diversity in marine bacteria
AuthorsRoss, Avena C.
Kersten, Roland D.
Al-Suwailem, Abdulaziz M.
Dorrestein, Pieter C.
Moore, Bradley S.
Online Publication Date2013-01-11
Print Publication Date2013-01-23
Embargo End Date2013-12-27
Permanent link to this recordhttp://hdl.handle.net/10754/562616
MetadataShow full item record
AbstractThalassospiramides A and B are immunosuppressant cyclic lipopeptides first reported from the marine α-proteobacterium Thalassospira sp. CNJ-328. We describe here the discovery and characterization of an extended family of 14 new analogues from four Tistrella and Thalassospira isolates. These potent calpain 1 protease inhibitors belong to six structure classes in which the length and composition of the acylpeptide side chain varies extensively. Genomic sequence analysis of the thalassospiramide-producing microbes revealed related, genus-specific biosynthetic loci encoding hybrid nonribosomal peptide synthetase/polyketide synthases consistent with thalassospiramide assembly. The bioinformatics analysis of the gene clusters suggests that structural diversity, which ranges from the 803.4 Da thalassospiramide C to the 1291.7 Da thalassospiramide F, results from a complex sequence of reactions involving amino acid substrate channeling and enzymatic multimodule skipping and iteration. Preliminary biochemical analysis of the N-terminal nonribosomal peptide synthetase module from the Thalassospira TtcA megasynthase supports a biosynthetic model in which in cis amino acid activation competes with in trans activation to increase the range of amino acid substrates incorporated at the N terminus. © 2012 American Chemical Society.
SponsorsThe authors gratefully acknowledge W. Fenical from UCSD for Thalassospira sp. CNJ-328 and E Mann from the Skidaway Institute of Oceanography for Thalassospira sp. TrichSKD 10. Tistrella bauzanensis TIO7329 was generously provided from the Third Institute of Oceanography, China PRC. J. P. Noel at the Salk Institute for Biological Sciences kindly provided access to the Ion Torrent sequencing instrument. Financial support was provided by the China Ocean Mineral Resources Research and Development Association (DY125-15-T-02), the King Abdullah University of Science and Technology (SA-00040/UK-00016 to P.Y.Q,), and the NIH (GM97509 to B.S.M. and P.C.D.).
PublisherAmerican Chemical Society (ACS)
PubMed Central IDPMC3563429
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