Evaluation of a concerted vs. sequential oxygen activation mechanism in α-ketoglutarate–dependent nonheme ferrous enzymes
Serra Goudarzi, Shyam R. Iyer, Jeffrey T. Babicz, James J. Yan, Günther H. Peters, Hans E. M. Christensen, Britt Hedman, Keith O. Hodgson, Edward I. Solomon
Abstract
Significance Many iron-dependent enzymes utilize molecular oxygen to functionalize inert C–H bonds in biology. Nonheme ferrous enzymes perform these reactions by reducing dioxygen, often in the presence of a sacrificial electron donor, to form a reactive intermediate that converts substrate to product. In α-ketoglutarate (αKG)–dependent enzymes, there has been discussion on the necessity of substrate prebinding to the αKG-bound ferrous center for productive chemistry. This study demonstrates that, when substrate is not prebound to the enzyme, the species generated in the reaction with dioxygen is not competent to perform hydrogen atom abstraction from the substrate. In contrast, when both cosubstrates are prebound to the enzyme, efficient coupling between dioxygen reduction and substrate oxidation is observed, leading to productive chemistry.