![]() If so, CO could compete with the binding of O 2 to ferrous verdoheme, the next step in conversion of verdoheme to biliverdin-iron chelate ( 5). The reaction intermediates shown in Figure 1 do not dissociate from HO during the reaction, which means that CO produced with verdoheme may still be present at the subsequent reaction step. Because CO preferentially binds to the ferrous heme iron and competes with binding of O 2, CO produced during the HO reaction is potentially a powerful inhibitor. Three molecules of O 2 are required for a complete reaction cycle, which occurs without release of the reaction intermediates derived from heme. The HO reaction proceeds via a multi-step mechanism and continuous availability of O 2 is important for the overall reaction ( Figure 1). Although CO is generally toxic, a small amount of CO is proposed to be involved in physiological processes such as anti-inflammation, anti-apoptosis, anti-proliferation, and vasodilation ( 4). The major physiological roles of HO in mammals are the recycling of iron, defense against oxidative stress, and the generation of CO as a signal transmitter. Heme oxygenase (HO) catalyzes the degradation of heme to biliverdin, ferrous iron, and carbon monoxide (CO) using reducing equivalents and molecular oxygen (O 2) ( 1– 3). ![]() The difference Fourier maps also suggest new routes for CO migration. Protein motions even at cryogenic temperature imply that CO-bound heme-HO-1 is severely constrained (as in ligand binding to the T-state of hemoglobin), indicating that CO binding to the heme-HO-1 complex is specifically inhibited by steric hindrance. No such changes are observed upon O 2 photolysis, consistent with the structures of the ligand-free, O 2-bound and CO-bound forms. Moreover, difference Fourier maps comparing the structures before and after CO photolysis at temperatures below 160 K clearly show structural changes such as movement of the distal F-helix upon CO photolysis. Here we determine the crystal structure of the O 2-bound form at 1.8 Å resolution and reveal the structural changes that are specific to CO binding. However, we have not yet identified those changes that are specific to CO binding and do not occur upon O 2 binding. Previously we demonstrated large conformational changes in the heme-HO-1 complex upon CO binding that arise from steric hindrance between CO bound to the heme iron and Gly-139. Because O 2 is required for the HO reaction, HO must discriminate effectively between CO and O 2 and thus escape product inhibition. It is well known that CO has a higher affinity for heme iron than does molecular oxygen (O 2), therefore CO is potentially toxic. Heme oxygenase (HO) catalyzes heme degradation, one of whose products is carbon monoxide (CO).
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