Drosophila melanogaster nonribosomal peptide synthetase Ebony encodes an atypical condensation domain

Thierry Izoré, Julien Tailhades, Mathias Henning Hansen, Joe A. Kaczmarski, Colin J. Jackson, Max J. Cryle

Research output: Contribution to journalArticleResearchpeer-review

Abstract

The protein Ebony from Drosophila melanogaster plays a central role in the regulation of histamine and dopamine in various tissues through condensation of these amines with β-alanine. Ebony is a rare example of a nonribosomal peptide synthetase (NRPS) from a higher eukaryote and contains a C-terminal sequence that does not correspond to any previously characterized NRPS domain. We have structurally characterized this C-terminal domain and have discovered that it adopts the aryl-alkylamine-N-acetyl transferase (AANAT) fold, which is unprecedented in NRPS biology. Through analysis of ligand-bound structures, activity assays, and binding measurements, we have determined how this atypical condensation domain is able to provide selectivity for both the carrier protein-bound amino acid and the amine substrates, a situation that remains unclear for standard condensation domains identified to date from NRPS assembly lines. These results demonstrate that the C terminus of Ebony encodes a eukaryotic example of an alternative type of NRPS condensation domain; they also illustrate how the catalytic components of such assembly lines are significantly more diverse than a minimal set of conserved functional domains.

Original languageEnglish
Pages (from-to)2913-2918
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number8
DOIs
Publication statusPublished - 19 Feb 2019

Keywords

  • Aryl-alkylamine N-acetyl transferase
  • C domain
  • Condensation reaction
  • Nonribosomal peptide synthetase
  • NRPS

Cite this

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title = "Drosophila melanogaster nonribosomal peptide synthetase Ebony encodes an atypical condensation domain",
abstract = "The protein Ebony from Drosophila melanogaster plays a central role in the regulation of histamine and dopamine in various tissues through condensation of these amines with β-alanine. Ebony is a rare example of a nonribosomal peptide synthetase (NRPS) from a higher eukaryote and contains a C-terminal sequence that does not correspond to any previously characterized NRPS domain. We have structurally characterized this C-terminal domain and have discovered that it adopts the aryl-alkylamine-N-acetyl transferase (AANAT) fold, which is unprecedented in NRPS biology. Through analysis of ligand-bound structures, activity assays, and binding measurements, we have determined how this atypical condensation domain is able to provide selectivity for both the carrier protein-bound amino acid and the amine substrates, a situation that remains unclear for standard condensation domains identified to date from NRPS assembly lines. These results demonstrate that the C terminus of Ebony encodes a eukaryotic example of an alternative type of NRPS condensation domain; they also illustrate how the catalytic components of such assembly lines are significantly more diverse than a minimal set of conserved functional domains.",
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Drosophila melanogaster nonribosomal peptide synthetase Ebony encodes an atypical condensation domain. / Izoré, Thierry; Tailhades, Julien; Hansen, Mathias Henning; Kaczmarski, Joe A.; Jackson, Colin J.; Cryle, Max J.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 8, 19.02.2019, p. 2913-2918.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Izoré, Thierry

AU - Tailhades, Julien

AU - Hansen, Mathias Henning

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AU - Jackson, Colin J.

AU - Cryle, Max J.

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AB - The protein Ebony from Drosophila melanogaster plays a central role in the regulation of histamine and dopamine in various tissues through condensation of these amines with β-alanine. Ebony is a rare example of a nonribosomal peptide synthetase (NRPS) from a higher eukaryote and contains a C-terminal sequence that does not correspond to any previously characterized NRPS domain. We have structurally characterized this C-terminal domain and have discovered that it adopts the aryl-alkylamine-N-acetyl transferase (AANAT) fold, which is unprecedented in NRPS biology. Through analysis of ligand-bound structures, activity assays, and binding measurements, we have determined how this atypical condensation domain is able to provide selectivity for both the carrier protein-bound amino acid and the amine substrates, a situation that remains unclear for standard condensation domains identified to date from NRPS assembly lines. These results demonstrate that the C terminus of Ebony encodes a eukaryotic example of an alternative type of NRPS condensation domain; they also illustrate how the catalytic components of such assembly lines are significantly more diverse than a minimal set of conserved functional domains.

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