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

C Dong; S Flecks; S Unversucht; C Haupt; K-H Van Pee; James Henderson Naismith

doi:10.1126/science.1116510

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

C Dong, S Flecks, S Unversucht, C Haupt, K-H Van Pee, James Henderson Naismith

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

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 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 FADH(2) reacts with O-2 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 language	English
Pages (from-to)	2216-2219
Number of pages	4
Journal	Science
Volume	309
Issue number	5744
DOIs	https://doi.org/10.1126/science.1116510
Publication status	Published - 30 Sept 2005

Keywords

BIOSYNTHETIC GENE-CLUSTER
PARA-HYDROXYBENZOATE HYDROXYLASE
CATION-PI INTERACTIONS
PSEUDOMONAS-FLUORESCENS
CHLOROPEROXIDASE
STREPTOMYCES
HALOGENATION
PYRROLNITRIN
REBECCAMYCIN
DERIVATIVES

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10.1126/science.1116510

Cite this

@article{a789126afce84c9abe513d5e285ee25d,

title = "Tryptophan 7-Halogenase (PrnA) Structure Suggests a Mechanism for Regioselective Chlorination",

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 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 FADH(2) reacts with O-2 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.",

keywords = "BIOSYNTHETIC GENE-CLUSTER, PARA-HYDROXYBENZOATE HYDROXYLASE, CATION-PI INTERACTIONS, PSEUDOMONAS-FLUORESCENS, CHLOROPEROXIDASE, STREPTOMYCES, HALOGENATION, PYRROLNITRIN, REBECCAMYCIN, DERIVATIVES",

author = "C Dong and S Flecks and S Unversucht and C Haupt and {Van Pee}, K-H and Naismith, {James Henderson}",

year = "2005",

month = sep,

day = "30",

doi = "10.1126/science.1116510",

language = "English",

volume = "309",

pages = "2216--2219",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

number = "5744",

}

TY - JOUR

T1 - Tryptophan 7-Halogenase (PrnA) Structure Suggests a Mechanism for Regioselective Chlorination

AU - Dong, C

AU - Flecks, S

AU - Unversucht, S

AU - Haupt, C

AU - Van Pee, K-H

AU - Naismith, James Henderson

PY - 2005/9/30

Y1 - 2005/9/30

N2 - Chlorinated natural products include vancomycin and cryptophycin A. Their biosynthesis involves regioselective chlorination by flavin-dependent halogenases. We report the structural characterization of tryptophan 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 FADH(2) reacts with O-2 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.

AB - Chlorinated natural products include vancomycin and cryptophycin A. Their biosynthesis involves regioselective chlorination by flavin-dependent halogenases. We report the structural characterization of tryptophan 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 FADH(2) reacts with O-2 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.

KW - BIOSYNTHETIC GENE-CLUSTER

KW - PARA-HYDROXYBENZOATE HYDROXYLASE

KW - CATION-PI INTERACTIONS

KW - PSEUDOMONAS-FLUORESCENS

KW - CHLOROPEROXIDASE

KW - STREPTOMYCES

KW - HALOGENATION

KW - PYRROLNITRIN

KW - REBECCAMYCIN

KW - DERIVATIVES

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UR - http://www.sciencemag.org/cgi/reprint/309/5744/2216.pdf

U2 - 10.1126/science.1116510

DO - 10.1126/science.1116510

M3 - Article

SN - 0036-8075

VL - 309

SP - 2216

EP - 2219

JO - Science

JF - Science

IS - 5744

ER -

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

Abstract

Keywords

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bb/c000080/1: The pyrrolnitrin biosynthetic pathway

BBSRC BBS/B/14426: SPORT

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

Abstract

Keywords

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Fingerprint

Projects

bb/c000080/1: The pyrrolnitrin biosynthetic pathway

BBSRC BBS/B/14426: SPORT

Cite this