Drosophila melanogaster nonribosomal peptide synthetase Ebony encodes an atypical condensation domain

Proc Natl Acad Sci U S A. 2019 Feb 19;116(8):2913-2918. doi: 10.1073/pnas.1811194116. Epub 2019 Jan 31.


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.

Keywords: C domain; NRPS; aryl-alkylamine N-acetyl transferase; condensation reaction; nonribosomal peptide synthetase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arylalkylamine N-Acetyltransferase / chemistry*
  • Catalytic Domain
  • Crystallography, X-Ray
  • DNA-Binding Proteins / chemistry*
  • Drosophila Proteins / chemistry*
  • Drosophila melanogaster / chemistry
  • Peptide Synthases / chemistry*
  • Protein Domains
  • Protein Folding
  • Protein Structure, Tertiary


  • DNA-Binding Proteins
  • Drosophila Proteins
  • e protein, Drosophila
  • Arylalkylamine N-Acetyltransferase
  • Peptide Synthases
  • non-ribosomal peptide synthase

Associated data

  • PDB/6DYM
  • PDB/6DYN
  • PDB/6DYO
  • PDB/6DYR
  • PDB/6DYS