Letter abstract
Nature Chemical Biology 3, 113 - 116 (2007)
Published online: 14 January 2007 | doi:10.1038/nchembio856
Two interconverting Fe(IV) intermediates in aliphatic chlorination by the halogenase CytC3
Danica P Galoni
1,
Eric W Barr2,
Christopher T Walsh1,
J Martin Bollinger, Jr2,3
&
Carsten Krebs2,3
Enzymatic incorporation of a halogen atom is a common feature in the biosyntheses of more than 4,500 natural products1, 2, 3, 4, 5. 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 
-ketoglutarate (KG, 1), chloride and oxygen6. To investigate the ability of these enzymes to functionalize unactivated methyl groups, we characterized the chlorination of the 
-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 KG-dependent hydroxylases.
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Ave., Boston, Massachusetts 02115, USA.
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.
- Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.
Correspondence to: Carsten Krebs2,3 e-mail: ckrebs@psu.edu
Correspondence to: J Martin Bollinger, Jr2,3 e-mail: jmb21@psu.edu
Correspondence to: Christopher T Walsh1 e-mail: christopher_walsh@hms.harvard.edu.
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