The nonribosomal peptide synthetase enzyme DdaD tethers N β-fumaramoyl-l -2,3-diaminopropionate for Fe(II)/α- ketoglutarate-dependent epoxidation by DdaC during dapdiamide antibiotic biosynthesis

Marie A. Hollenhorst, Stefanie B. Bumpus, Megan L. Matthews, Joseph M. Bollinger, Jr., Neil L. Kelleher, Christopher T. Walsh

Research output: Contribution to journalArticle

20 Scopus citations


The gene cluster from Pantoea agglomerans responsible for biosynthesis of the dapdiamide antibiotics encodes an adenylation-thiolation didomain protein, DdaD, and an Fe(II)/α-ketoglutarate-dependent dioxygenase homologue, DdaC. Here we show that DdaD, a nonribosomal peptide synthetase module, activates and sequesters Nβ-fumaramoyl-l-2,3-diaminopropionate as a covalently tethered thioester for subsequent oxidative modification of the fumaramoyl group. DdaC catalyzes Fe(II)- and α-ketoglutarate-dependent epoxidation of the covalently bound Nβ-fumaramoyl-l-2,3- diaminopropionyl-S-DdaD species to generate Nβ-epoxysuccinamoyl- DAP (DAP = 2,3-diaminopropionate) in thioester linkage to DdaD. After hydrolytic release, Nβ-epoxysuccinamoyl-DAP can be ligated to l-valine by the ATP-dependent ligase DdaF to form the natural antibiotic N β-epoxysuccinamoyl-DAP-Val.

Original languageEnglish (US)
Pages (from-to)15773-15781
Number of pages9
JournalJournal of the American Chemical Society
Issue number44
Publication statusPublished - Nov 10 2010


All Science Journal Classification (ASJC) codes

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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