Origin of Reactivity Differences Between Heme and Nonheme Iron(III)-Hydroperoxo Complexes

The cytochromes P450 are important enzymes in human physiology involved in biodegradation and biosynthesis pathways in the body.^1,2 They generally react with substrates in a catalytic cycle that includes two reduction and two proton transfer steps to form a high-valent iron(IV)-oxo heme cation radical species called Compound I.³ High-valent metal-oxo species are common intermediates in enzymatic processes and have been identified in heme as well as nonheme iron enzymes. Compound I is a versatile and efficient oxidant that is known to react with substrates via aliphatic hydroxylation, epoxidation, aromatic hydroxylation, alkane dehydrogenation, N-dealkylation, sulfoxidation etc. Many of these processes involve the reduction of Compound I; unfortunately, Compound I is short-lived, which makes experimental studies in the field complicated. To overcome this, we have done computational studies on enzymatic heme enzymes as well as synthetic model porphyrins and phthalocyanines with the aim to gain insight into the intricate details of the oxidant to gain insight into the electrochemistry of the active species and the catalyzed reaction mechanism. In the past, these studies assisted experimental efforts in the field and made predictions of reaction mechanisms. It was, for instance, shown that the precursor of Compound I in the catalytic cycle, namely Compound 0, is catalytically inactive for epoxidation, sulfoxidation and aromatic hydroxylation reactions. However, in a recent twist of events, our group showed that nonheme iron(III)-hydroperoxo can be catalytically active.⁴ To understand the difference in activity between heme and nonheme iron(III)-hydroperoxo, we studied the mechanisms of aromatic hydroxylation and haloperoxidation. These combined experimental and computational studies gave insight into the effects of axial and equatorial ligands on the chemical and catalytic properties of Compound 0 and Compound I. In addition, our studies established the effects of environmental perturbations on the properties and reactivities of Compound I, including hydrogen bonding interactions and secondary sphere amino acid interactions.

References:

1. P. R. Ortiz de Montellano (Ed.), Cytochrome P450: Structure, Mechanism and Biochemistry. 3rd ed.; Kluwer Academic/Plenum Publishers, New York, 2005.
2. K. M. Kadish, K. M. Smith, R. Guilard (Eds.), Handbook of Porphyrin Science. World Scientific Publishing Co., New Jersey, 2010.
3. S. P. de Visser, D. Kumar (Eds.), Iron-containing enzymes: Versatile catalysts of hydroxylation reaction in nature. RSC Publishing, Cambridge (UK), 2011.
4. A. S. Faponle, M. G. Quesne, C. V. Sastri, F. Banse, S. P. de Visser, Chem. Eur. J. 2014, in press.