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Science 30 September 2005:
Vol. 309. no. 5744, pp. 2216 - 2219
DOI: 10.1126/science.1116510
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Reports

Tryptophan 7-Halogenase (PrnA) Structure Suggests a Mechanism for Regioselective Chlorination

Changjiang Dong,1 Silvana Flecks,2 Susanne Unversucht,2 Caroline Haupt,2 Karl-Heinz van Pée,2 James H. Naismith1*

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.

1 Centre for Biomolecular Sciences, EaStchem, University of St. Andrews, St. Andrews KY16 9ST, UK.
2 Institut für Biochemie, Technische Universität Dresden, D-01062 Dresden, Germany.

* To whom correspondence should be addressed.

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THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Detection, Distribution, and Organohalogen Compound Discovery Implications of the Reduced Flavin Adenine Dinucleotide-Dependent Halogenase Gene in Major Filamentous Actinomycete Taxonomic Groups.
P. Gao and Y. Huang (2009)
Appl. Envir. Microbiol. 75, 4813-4820
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Contribution of Flavin Covalent Linkage with Histidine 99 to the Reaction Catalyzed by Choline Oxidase.
O. Quaye, S. Cowins, and G. Gadda (2009)
J. Biol. Chem. 284, 16990-16997
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Halogenase Genes in Nonribosomal Peptide Synthetase Gene Clusters of Microcystis (Cyanobacteria): Sporadic Distribution and Evolution.
S. Cadel-Six, C. Dauga, A. M. Castets, R. Rippka, C. Bouchier, N. Tandeau de Marsac, and M. Welker (2008)
Mol. Biol. Evol. 25, 2031-2041
   Abstract »    Full Text »    PDF »
Crystal Structure of the Oxygenase Component (HpaB) of the 4-Hydroxyphenylacetate 3-Monooxygenase from Thermus thermophilus HB8.
S.-H. Kim, T. Hisano, K. Takeda, W. Iwasaki, A. Ebihara, and K. Miki (2007)
J. Biol. Chem. 282, 33107-33117
   Abstract »    Full Text »    PDF »
Structure of the monooxygenase component of a two-component flavoprotein monooxygenase.
A. Alfieri, F. Fersini, N. Ruangchan, M. Prongjit, P. Chaiyen, and A. Mattevi (2007)
PNAS 104, 1177-1182
   Abstract »    Full Text »    PDF »


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Science. ISSN 0036-8075 (print), 1095-9203 (online)