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; J. Martin Bollinger; Neil L. Kelleher; Christopher T. Walsh

doi:10.1021/ja1072367

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, J. Martin Bollinger, Neil L. Kelleher, Christopher T. Walsh

Research output: Contribution to journal › Article › peer-review

26 Scopus citations

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 N_β-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 N_β-fumaramoyl-l-2,3- diaminopropionyl-S-DdaD species to generate N_β-epoxysuccinamoyl- DAP (DAP = 2,3-diaminopropionate) in thioester linkage to DdaD. After hydrolytic release, N_β-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 language	English (US)
Pages (from-to)	15773-15781
Number of pages	9
Journal	Journal of the American Chemical Society
Volume	132
Issue number	44
DOIs	https://doi.org/10.1021/ja1072367
State	Published - Nov 10 2010

All Science Journal Classification (ASJC) codes

Catalysis
Chemistry(all)
Biochemistry
Colloid and Surface Chemistry

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Hollenhorst, M. A., Bumpus, S. B., Matthews, M. L., Bollinger, J. M., Kelleher, N. L., & Walsh, C. T. (2010). 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. Journal of the American Chemical Society, 132(44), 15773-15781. https://doi.org/10.1021/ja1072367

@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, {J. Martin} and Kelleher, {Neil L.} and Walsh, {Christopher T.}",

year = "2010",

month = nov,

day = "10",

doi = "10.1021/ja1072367",

language = "English (US)",

volume = "132",

pages = "15773--15781",

journal = "Journal of the American Chemical Society",

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publisher = "American Chemical Society",

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Hollenhorst, MA, Bumpus, SB, Matthews, ML, Bollinger, JM, Kelleher, NL & Walsh, CT 2010, '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', Journal of the American Chemical Society, vol. 132, no. 44, pp. 15773-15781. https://doi.org/10.1021/ja1072367

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. et al.

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

Research output: Contribution to journal › Article › peer-review

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, J. Martin

AU - Kelleher, Neil L.

AU - Walsh, Christopher T.

PY - 2010/11/10

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N2 - 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.

AB - 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.

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JO - Journal of the American Chemical Society

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Hollenhorst MA, Bumpus SB, Matthews ML, Bollinger JM, Kelleher NL, Walsh CT. 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. Journal of the American Chemical Society. 2010 Nov 10;132(44):15773-15781. doi: 10.1021/ja1072367

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

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