Two interconverting Fe(IV) intermediates in aliphatic chlorination by the halogenase CytC3

Danica P. Galonić, Eric W. Barr, Christopher T. Walsh, Joseph M. Bollinger, Jr., Carsten Krebs

Research output: Contribution to journalArticle

220 Citations (Scopus)

Abstract

Enzymatic incorporation of a halogen atom is a common feature in the biosyntheses of more than 4,500 natural products. Halogenation of unactivated carbon centers in the biosyntheses of several compounds of nonribosomal peptide origin is carried out by a class of mononuclear nonheme iron enzymes that require α-ketoglutarate (αKG, 1), chloride and oxygen. To investigate the ability of these enzymes to functionalize unactivated methyl groups, we characterized the chlorination of the γ-methyl substituent of L-2-aminobutyric acid (L-Aba, 2) attached to the carrier protein CytC2 by iron halogenase (CytC3) from soil Streptomyces sp. We identified an intermediate state comprising two high-spin Fe(IV) complexes in rapid equilibrium. At least one of the Fe(IV) complexes abstracts hydrogen from the substrate. The demonstration that chlorination proceeds through an Fe(IV) intermediate that cleaves a C-H bond reveals the mechanistic similarity of aliphatic halogenases to the iron- and αKG-dependent hydroxylases.

Original languageEnglish (US)
Pages (from-to)113-116
Number of pages4
JournalNature Chemical Biology
Volume3
Issue number2
DOIs
StatePublished - Jan 1 2007

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Halogenation
Iron
Halogens
Streptomyces
Enzymes
Mixed Function Oxygenases
Biological Products
Chlorides
Hydrogen
Carrier Proteins
Soil
Carbon
Oxygen
Peptides

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Cite this

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abstract = "Enzymatic incorporation of a halogen atom is a common feature in the biosyntheses of more than 4,500 natural products. Halogenation of unactivated carbon centers in the biosyntheses of several compounds of nonribosomal peptide origin is carried out by a class of mononuclear nonheme iron enzymes that require α-ketoglutarate (αKG, 1), chloride and oxygen. To investigate the ability of these enzymes to functionalize unactivated methyl groups, we characterized the chlorination of the γ-methyl substituent of L-2-aminobutyric acid (L-Aba, 2) attached to the carrier protein CytC2 by iron halogenase (CytC3) from soil Streptomyces sp. We identified an intermediate state comprising two high-spin Fe(IV) complexes in rapid equilibrium. At least one of the Fe(IV) complexes abstracts hydrogen from the substrate. The demonstration that chlorination proceeds through an Fe(IV) intermediate that cleaves a C-H bond reveals the mechanistic similarity of aliphatic halogenases to the iron- and αKG-dependent hydroxylases.",
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Two interconverting Fe(IV) intermediates in aliphatic chlorination by the halogenase CytC3. / Galonić, Danica P.; Barr, Eric W.; Walsh, Christopher T.; Bollinger, Jr., Joseph M.; Krebs, Carsten.

In: Nature Chemical Biology, Vol. 3, No. 2, 01.01.2007, p. 113-116.

Research output: Contribution to journalArticle

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