Chameleonic nature of hydroxyheme in heme oxygenase and its reactivity: a density functional theory study

Iron hydroxyheme is an intermediate in heme degradation that binds to HO-1 in a five-coordinated fashion wherein the fifth ligand is His25. The structure and reactivity of hydroxyheme have been investigated using the B3LYP*, OPBE, and CASSCF methods with the 6-31+G* and 6-311+G** basis sets. Hydroxyheme [(Im)Fe(II)(POH)] (POH is the hydroxyporphyrin) is readily oxidized to oxophlorin [(Im)Fe(III)(PO)] (PO is the oxophlorin trianion) in the protein heme oxygenase. A computational study in the gas phase has shown that (6)[(Im)Fe(II)(POH)] loses one electron from its a2u orbital in the presence of O2 and produces [(Im)Fe(II)(PO(•))]a2u(PO(•) is the oxophlorin dianion radical) in the sextet ground state with a ferrous keto π-neutral radical structure and dxy(2)a2u(1)dyz(1)dxz(1)σ*z2(1)d(x(2)-y(2))(1) electronic configuration. There is a closely lying exited state accompanying this ferrous keto π-neutral radical that has a high-spin ferric keto anion form of (6)[(Im)Fe(III)(PO)]xy with a2u(2)dxy(1)dyz(1)dxz(1)σ*z2(1)d(x(2)-y(2))(1) electronic configuration. In the protein environment with a dipole moment larger than 5.7, the ground state is reversed and (6)[(Im)Fe(III)(PO)]xy is at least 1.47 kcal/mol lower than the ferrous π-neutral radical of (6)[(Im)Fe(II) (PO(•))]a2u. The interaction of H2O, O2, and CO with iron oxophlorin will shift the electronic structure toward the formation of a keto π-neutral radical resonance form in the following order: CO > O2 > H2O.