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Two interconverting Fe(IV) intermediates in aliphatic chlorination by the halogenase CytC3
Danica P Galonić1, Eric W Barr, Christopher T Walsh
1Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Ave., Boston, Massachusetts 02115, USA.
Nature Chemical Biology
|January 16, 2007
Summary
Iron halogenase enzymes functionalize unactivated methyl groups by abstracting hydrogen via an Fe(IV) intermediate. This reveals mechanistic similarities between aliphatic halogenases and iron-dependent hydroxylases.
Area of Science:
- Biochemistry
- Enzymology
- Natural Product Biosynthesis
Background:
- Enzymatic halogenation is crucial for synthesizing over 4,500 natural products.
- Mononuclear nonheme iron enzymes utilizing alpha-ketoglutarate (alphaKG), chloride, and oxygen halogenate unactivated carbon centers in nonribosomal peptides.
Purpose of the Study:
- Investigate the capacity of iron halogenases to functionalize unactivated methyl groups.
- Characterize the chlorination mechanism of L-2-aminobutyric acid (L-Aba) by iron halogenase CytC3.
Main Methods:
- Enzymatic assay using CytC3 from Streptomyces sp. to chlorinate L-Aba attached to the CytC2 carrier protein.
- Spectroscopic identification of reaction intermediates.
Main Results:
- Identified a reaction intermediate involving two high-spin Fe(IV) complexes in rapid equilibrium.
- Demonstrated that at least one Fe(IV) complex abstracts hydrogen from the substrate's methyl group.
- Confirmed C-H bond cleavage during the chlorination process.
Conclusions:
- Aliphatic halogenases employ an Fe(IV) intermediate to cleave C-H bonds, similar to iron- and alphaKG-dependent hydroxylases.
- This study elucidates a key step in the biosynthesis of halogenated natural products.
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