A new look at the role of thiolate ligation in cytochrome P450

Protonated ferryl (or iron(IV) hydroxide) intermediates have been characterized in several thiolate-ligated heme proteins that are known to catalyze C-H bond activation. The basicity of the ferryl intermediates in these species has been proposed to play a critical role in facilitating this chemistry, allowing hydrogen abstraction at reduction potentials below those that would otherwise lead to oxidative degradation of the enzyme. In this contribution, we discuss the events that led to the assignment and characterization of the unusual iron(IV) hydroxide species, highlighting experiments that provided a quantitative measure of the ferryl basicity, the iron(IV) hydroxide pKa. We then turn to the importance of the iron(IV) hydroxide state, presenting a new way of looking at the role of thiolate ligation in these systems.