Heme oxygenase (HO) plays a central role in heme catabolism, which is involved in keeping iron homeostasis, defense for oxidative stress, and signal transduction in mammals. HO catalyzes the site-specific cleavage of heme to produce biliverdin IXα, CO, and iron using reducing equivalents and O2. To address the reaction mechanism of HO, I determined the crystal structures of rat HO-1 in substrate-free form, heme-bound form, O2-analog bound forms, and biliverdiniron chelate bound form. These structures revealed that the narrow distal pocket of HO limits the direction of distal ligand by which the site-specific cleavage is allowed. Moreover, I discuss how HO incorporates heme and dissociates iron and biliverdin as well. I also determined the crystal structure of rat heme-HO-1 complex in CO bound form and succeeded in trapping an intermediate structure during the CO releasing step. Discrimination mechanism between O2 and CO by HO is discussed based on these structures. Finally I refer to a possibility of development of novel inhibitors to HO using imidazole-dioxolane compounds.
