Tryptophan 7-halogenase (PrnA) structure suggests a mechanism for regioselective chlorination

Changjiang Dong, Silvana Flecks, Susanne Unversucht, Caroline Haupt, Karl-Heinz van Pée, James H Naismith

Research output: Contribution to journalArticlepeer-review

267 Citations (Scopus)

Abstract

Chlorinated natural products include vancomycin and cryptophycin A. Their biosynthesis involves regioselective chlorination by flavin-dependent halogenases. We report the structural characterization of tryptophan 7-halogenase (PrnA), which regioselectively chlorinates tryptophan. Tryptophan and flavin adenine dinucleotide (FAD) are separated by a 10 angstrom-long tunnel and bound by distinct enzyme modules. The FAD module is conserved in halogenases and is related to flavin-dependent monooxygenases. On the basis of biochemical studies, crystal structures, and by analogy with monooxygenases, we predict that FADH2 reacts with O2 to make peroxyflavin, which is decomposed by Cl-. The resulting HOCl is guided through the tunnel to tryptophan, where it is activated to participate in electrophilic aromatic substitution.
Original languageEnglish
Pages (from-to)2216-9
Number of pages4
JournalScience
Volume309
Issue number5744
DOIs
Publication statusPublished - 30 Sep 2005

Keywords

  • Amino Acid Sequence
  • Binding Sites
  • Chlorides
  • Crystallography, X-Ray
  • Dimerization
  • Flavin-Adenine Dinucleotide
  • Hydrogen Bonding
  • Hypochlorous Acid
  • Indoles
  • Models, Molecular
  • Molecular Sequence Data
  • Oxidation-Reduction
  • Oxidoreductases
  • Oxygen
  • Protein Conformation
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Pseudomonas fluorescens
  • Tryptophan

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