Structure and catalytic mechanism of heme oxygenase

Abstract

Covering: up to 2006

Heme oxygenase (HO) catalyzes O₂-dependent regiospecific conversion of heme to biliverdin, CO and free Fe(II). The heme group is tightly sandwiched between the “proximal” and “distal” helices with a neutral imidazole of His as an axial ligand. In the ferrous form, both helices move closer to the heme group, and O₂ binds with an acute Fe–O–O angle of ∼110°, the distal helix restricts the O–O bond direction placing the terminal oxygen atom close to the α-meso-carbon. The bound O₂ is stabilized by hydrogen bonds with a distal Gly amide nitrogen and the nearby H₂O, the latter of which is a part of an extended distal pocket hydrogen bonding network linked by a conserved distal Asp. The hydrogen bonding network functions as a conduit for transferring protons required for the formation of the ferric hydroperoxo, generated by one-electron reduction of the oxy form, and also for the activation of the hydroperoxo, leading to the selective hydroxylation of the heme α-meso-carbon. The ferric hydroperoxo active species could not be formed upon loss of the nearby H₂O, indicating a critical role of this H₂O molecule in the meso-carbon hydroxylation. Ferrous verdoheme formation proceeds by reaction of the ferrous porphyrin neutral radical of ferric α-meso-hydroxyheme with O₂ and one electron. Ferrous verdoheme iron reacts with O₂ to form a reaction intermediate, reduction of which affords biliverdin. Proton transfer by the distal pocket hydrogen bonding network facilitates conversion of verdoheme to biliverdin. HO heme catabolism is realized by the salient HO protein structure that enables conversion of heme, which is rather inert, into reactive hydroxyheme and verdoheme intermediates.