Dynamic metal coordination controls chemoselectivity in a radical halogenase.

Area of Science:

• Biocatalysis
• Enzyme Mechanisms
• Chemical Synthesis

Background:

• Nonheme iron enzymes activate inert C(sp3)-H bonds, offering a biocatalytic route to complex molecules.
• Fe(II)/α-ketoglutarate-dependent radical halogenases facilitate diverse anion transfer post C-H activation.

Purpose of the Study:

• To investigate the mechanisms driving radical rebound bifurcation in Fe(II)/α-ketoglutarate-dependent radical halogenases.
• To elucidate the role of the metal coordination sphere and hydrogen-bonding networks in enzyme catalysis.
• To identify intermediates in the O2 activation pathway of these enzymes.

Main Methods:

• Experimental studies on Fe(II)/α-ketoglutarate-dependent radical halogenases.
• Crystallographic analysis to determine enzyme structures.
• Investigation of radical rebound dynamics and hydrogen-bonding interactions.

Main Results:

• Experimental evidence shows that dynamic metal coordination sphere reorganization and a two-residue hydrogen-bonding network drive radical rebound bifurcation after H-atom abstraction.
• Crystallographic data reveal an early peroxyhemiketal intermediate in the O2 activation pathway.
• The findings highlight the interplay between the enzyme's dynamic structure and its catalytic function.

Conclusions:

• The study provides a framework for understanding the evolution of catalytic versatility in nonheme iron enzymes.
• Insights gained can guide the rational design of novel biocatalysts with expanded reaction scopes.
• Understanding these mechanisms is crucial for advancing synthetic chemistry and biocatalysis.