title: O(2)- and H(2)O(2)-dependent verdoheme degradation by heme oxygenase: reaction mechanisms and potential physiological roles of the dual pathway degradation.
abstract: Heme oxygenase (HO) catalyzes the catabolism of heme to biliverdin, CO, and a free iron through three successive oxygenation steps. The third oxygenation, oxidative degradation of verdoheme to biliverdin, has been the least understood step despite its importance in regulating HO activity. We have examined in detail the degradation of a synthetic verdoheme IXalpha complexed with rat HO-1. Our findings include: 1) HO degrades verdoheme through a dual pathway using either O(2) or H(2)O(2); 2) the verdoheme reactivity with O(2) is the lowest among the three O(2) reactions in the HO catalysis, and the newly found H(2)O(2) pathway is approximately 40-fold faster than the O(2)-dependent verdoheme degradation; 3) both reactions are initiated by the binding of O(2) or H(2)O(2) to allow the first direct observation of degradation intermediates of verdoheme; and 4) Asp(140) in HO-1 is critical for the verdoheme degradation regardless of the oxygen source. On the basis of these findings, we propose that the HO enzyme activates O(2) and H(2)O(2) on the verdoheme iron with the aid of a nearby water molecule linked with Asp(140). These mechanisms are similar to the well established mechanism of the first oxygenation, meso-hydroxylation of heme, and thus, HO can utilize a common architecture to promote the first and third oxygenation steps of the heme catabolism. In addition, our results infer the possible involvement of the H(2)O(2)-dependent verdoheme degradation in vivo, and potential roles of the dual pathway reaction of HO against oxidative stress are proposed.
authors.affiliation: Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Katahira, Aoba, Sendai 980-8577, Japan.
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Matsui
authors.forename: Aya
authors.initials: A
authors.lastname: Nakajima
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fujii
authors.forename: Kathryn Mansfield
authors.initials: KM
authors.lastname: Matera
authors.forename: Catharina T
authors.initials: CT
authors.lastname: Migita
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yoshida
authors.forename: Masao
authors.initials: M
authors.lastname: Ikeda-Saito
mesh_terms: D000818:Animals; D001664:Biliverdine / Q000378:metabolism; D002384:Catalysis; D002851:Chromatography, High Pressure Liquid; D006418:Heme / Q000031:analogs & derivatives* / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D007501:Iron / Q000378:metabolism; D013058:Mass Spectrometry; D016297:Mutagenesis, Site-Directed; D016877:Oxidants / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010100:Oxygen / Q000494:pharmacology*; D051381:Rats; D015398:Signal Transduction
chemical_list: D016877:Oxidants; C099547:verdoheme; D006418:Heme; D006861:Hydrogen Peroxide; D007501:Iron; D051547:Heme Oxygenase-1; D001664:Biliverdine; D010100:Oxygen