Myeloperoxidase acts as a source of free iron during steady-state catalysis by a feedback inhibitory pathway.
Myeloperoxidase acts as a source of free iron during steady-state catalysis by a feedback inhibitory pathway.
复制标题
DOI：
10.1016/j.freeradbiomed.2013.04.009
复制
发表时间：
2013-10
影响因子：
7.4
通讯作者：
Abu-Soud, Husam M.
中科院分区：
文献类型：
--
作者：
Maitra, Dhiman;Shaeib, Faten;Abdulhamid, Ibrahim;Abdulridha, Rasha M.;Saed, Ghassan M.;Diamond, Michael P.;Pennathur, Subramaniam;Abu-Soud, Husam M.
关键词：
髓过氧化物酶（MPO）是一种含血红素的酶，可从氯化物（Cl−）和过氧化氢（H2 O2）生成次氯酸（HOCl）。它与几种慢性炎症性疾病如心血管和肺部疾病以及癌症的病理学有关。最近我们发现HOCl可以破坏血红素蛋白的血红素辅基。在这里，我们研究了稳态催化过程中形成的HOCl是否能够破坏MPO血红素部分，从而作为游离铁的主要来源。在MPO稳态HOCl合成过程中记录的紫外可见光谱和H2 O2特异性电极测量结果表明，多次加入H2 O2（10 μM）后，MPO血红素破坏程度增加，使酶无法发挥最大活性（80-90%抑制）。MPO血红素的破坏只发生在Cl−的存在下。停流测量结果表明，HOCl介导的MPO血红素破坏是复杂的，并通过瞬时铁物种的形成和衰变动力学表明，它参与血红素破坏沿着随后的游离铁释放。MPO血红素消耗证实了游离铁的积累利用ferrozine测定。次氯酸一旦产生，首先在溶液中作为整体平衡，然后结合血红素铁并引发血红素破坏。通过清除HOCl从MPO环境中消除HOCl，使可能在催化过程中形成的MPO-化合物I-Cl复合物不稳定，和/或抑制MPO催化活性，部分或完全保护MPO免受HOCl侵害。总的来说，这项研究阐明了MPO和HOCl之间的双向关系，这突出了MPO作为游离铁来源的潜在作用。
Myeloperoxidase (MPO) is a heme-containing enzyme that generates hypochlorous acid (HOCl) from chloride (Cl−) and hydrogen peroxide (H2O2). It is implicated in the pathology of several chronic inflammatory conditions such as cardiovascular and pulmonary diseases and cancer. Recently we have shown that HOCl can destroy the heme prosthetic group of hemoproteins. Here, we investigated whether the HOCl formed during steady-state catalysis is able to destroy the MPO heme moiety and thereby function as a major source of free iron. UV–visible spectra and H2O2-specific electrode measurements recorded during steady-state HOCl synthesis by MPO showed that the degree of MPO heme destruction increased after multiple additions of H2O2 (10 μM), precluding the enzyme from functioning at maximum activity (80–90% inhibition). MPO heme destruction occurred only in the presence of Cl−. Stopped-flow measurements revealed that the HOCl-mediated MPO heme destruction was complex and occurred through transient ferric species whose formation and decay kinetics indicated it participates in heme destruction along with subsequent free iron release. MPO heme depletion was confirmed by the buildup of free iron utilizing the ferrozine assay. Hypochlorous acid, once generated, first equilibrates in the solution as a whole before binding to the heme iron and initiating heme destruction. Eliminating HOCl from the MPO milieu by scavenging HOCl, destabilizing the MPO–Compound I–Cl complex that could be formed during catalysis, and/or inhibiting MPO catalytic activity partially or completely protects MPO from HOCl insults. Collectively, this study elucidates the bidirectional relationship between MPO and HOCl, which highlights the potential role of MPO as a source of free iron.
登录
查看更多内容
影响因子：
7.4
作者：
Galijasevic, Semira;Maitra, Dhiman;Lu, Tun;Sliskovic, Inga;Abdulhamid, Ibrahim;Abu-Soud, Husam M.
通讯作者：
Abu-Soud, Husam M.
DOI：
10.1046/j.1432-1327.2000.01491.x
发表时间：
2000-10-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Furtmüller, PC;Obinger, C;Dunford, HB
通讯作者：
Dunford, HB
影响因子：
4.1
作者：
Chapman, ALP;Winterbourn, CC;Kettle, AJ
通讯作者：
Kettle, AJ
DOI：
10.1111/j.1432-1033.1992.tb17097.x
发表时间：
1992-07-15
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
FLORIS, R;WEVER, R
通讯作者：
WEVER, R
DOI：
10.1016/0304-4165(96)00014-1
发表时间：
1996-08-13
影响因子：
3
作者：
Britigan, BE;Ratcliffe, HR;Rosen, GM
通讯作者：
Rosen, GM