Electronic Structure and Reaction Mechanism of Heme Peroxidases

The first step of the reaction mechanism of heme peroxidases is the formation of a high-valent iron oxo porphyrin intermediate named Compound I (Cpd I). Cpd I is either a porphyrin cation radical species (Por(+)-Fe(IV)=O) such as in Horse radish peroxidase (HRP) and ascorbate peroxidase (APX), or a protein-based radical (Por-Fe(IV)=O, aa(+)), such as in cytochrome c peroxidase (CcP) and bifunctional peroxidases (i.e. catalase-peroxidases, KatGs) of some species. Knowledge of the electronic structure of Cpd I is a first step to understand the mechanism of the reaction. This is particularly interesting for KatGs, which are responsible for activating isoniazid, the frontline drug to treat tuberculosis. Recent QM/MM simulations on the mechanism of Cpd I formation in HRP, a classical monofunctional peroxidase, as well as the electronic structure of Cpd I of KatG, a bifunctional peroxidase, are discussed here.