Dynamic metal coordination controls chemoselectivity in radical halogenases.

Area of Science:

• Biochemistry and enzymology
• Chemical biology
• Organic synthesis

Background:

• Non-heme iron enzymes catalyze the activation of inert C(sp³)-H bonds, essential for metabolism, epigenetics, and signaling.
• Fe(II)/α-ketoglutarate-dependent radical halogenases are biocatalysts capable of anion transfer post C-H activation, offering synthetic utility.
• Understanding the mechanisms governing these enzymes is key to expanding their synthetic applications.

Purpose of the Study:

• To experimentally elucidate the factors driving the bifurcation of H-atom abstraction and radical rebound in Fe(II)/α-ketoglutarate-dependent radical halogenases.
• To identify the minimal amino acid residues responsible for the enzyme's catalytic plasticity and reaction scope.

Main Methods:

• Utilized experimental evidence to investigate the catalytic mechanism of Fe(II)/α-ketoglutarate-dependent radical halogenases.
• Focused on the roles of the dynamic metal coordination sphere and second-sphere hydrogen-bond networks in reaction pathway determination.

Main Results:

• Provided the first experimental evidence that both a dynamic metal coordination sphere and a second-sphere hydrogen-bond network govern the bifurcation of H-atom abstraction and radical rebound.
• Identified a minimal two-residue motif (Asn224 and Ile151) as necessary and sufficient for this process.

Conclusions:

• The identified minimal motif provides a new paradigm for understanding the evolution of catalytic plasticity in these enzymes.
• Offers insights into designing novel biocatalysts with expanded reaction scopes for C-H activation and functionalization.