O2- and H2O2-dependent verdoheme degradation by heme oxygenase -: Reaction mechanisms and potential physiological roles of the dual pathway degradation
O2- and H2O2-dependent verdoheme degradation by heme oxygenase -: Reaction mechanisms and potential physiological roles of the dual pathway degradation
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DOI：
10.1074/jbc.m503529200
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发表时间：
2005-11-04
影响因子：
4.8
通讯作者：
Ikeda-Saito, M
中科院分区：
文献类型：
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作者：
Matsui, T;Nakajima, A;Ikeda-Saito, M
血红素加氧酶（HO）通过三个连续的氧化步骤催化血红素催化胆绿素、CO和游离铁。第三个氧化，氧化降解的绿血红素胆绿素，一直是最不了解的步骤，尽管它在调节HO活性的重要性。我们详细研究了与大鼠HO-1复合的合成verdoheme IX alpha的降解。我们的研究结果包括：1）HO通过O-2或H_2O_2的双途径降解绿血红素，2）在HO催化的三种O-2反应中，绿血红素与O-2的反应性最低，新发现的H_2O_2途径比O-2依赖的绿血红素降解快40倍左右; 3）两个反应都是通过O-2或H2 O2的结合而引发的，从而允许第一次直接观察到绿血红素的降解中间体;和4）HO-1中的Asp（140）对于绿血红素的降解是关键的，无论氧源如何。基于这些研究结果，我们提出HO酶激活O-2和H2 O2的verdoheme铁与附近的水分子连接与Asp 140的援助。这些机制类似于第一氧化、血红素的内消旋羟基化的已确立的机制，因此，HO可以利用共同的结构来促进血红素催化剂的第一和第三氧化步骤。此外，我们的研究结果推断可能参与的H2 O2依赖的verdoheme降解在体内，和HO对抗氧化应激的双途径反应的潜在作用提出了建议。
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 IX alpha complexed with rat HO-1. Our findings include: 1) HO degrades verdoheme through a dual pathway using either O-2 or H2O2; 2) the verdoheme reactivity with O-2 is the lowest among the three O-2 reactions in the HO catalysis, and the newly found H2O2 pathway is similar to 40-fold faster than the O-2-dependent verdoheme degradation; 3) both reactions are initiated by the binding of O-2 or H2O2 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 H2O2 on the verdoheme iron with the aid of a nearby water molecule linked with Asp140. 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 H2O2-dependent verdoheme degradation in vivo, and potential roles of the dual pathway reaction of HO against oxidative stress are proposed.