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 Citations (Scopus)

Abstract

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
Volume132
Issue number44
DOIs
StatePublished - Nov 10 2010

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Peptide Synthases
Epoxidation
Biosynthesis
Antibiotics
Peptides
Enzymes
Pantoea
Anti-Bacterial Agents
Dioxygenases
Adenosinetriphosphate
Valine
Ligases
Multigene Family
Genes
Adenosine Triphosphate
Proteins

All Science Journal Classification (ASJC) codes

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

Cite this

@article{bc870eb87d494ef286fce9155297b9ec,
title = "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",
abstract = "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.",
author = "Hollenhorst, {Marie A.} and Bumpus, {Stefanie B.} and Matthews, {Megan L.} and {Bollinger, Jr.}, {Joseph M.} and Kelleher, {Neil L.} and Walsh, {Christopher T.}",
year = "2010",
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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. / Hollenhorst, Marie A.; Bumpus, Stefanie B.; Matthews, Megan L.; Bollinger, Jr., Joseph M.; Kelleher, Neil L.; Walsh, Christopher T.

In: Journal of the American Chemical Society, Vol. 132, No. 44, 10.11.2010, p. 15773-15781.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 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

AU - Hollenhorst, Marie A.

AU - Bumpus, Stefanie B.

AU - Matthews, Megan L.

AU - Bollinger, Jr., Joseph M.

AU - Kelleher, Neil L.

AU - Walsh, Christopher T.

PY - 2010/11/10

Y1 - 2010/11/10

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