Interactions of the Antimalarial Drug Methylene Blue with Methemoglobin and Heme Targets in Plasmodium falciparum: A Physico-Biochemical Study
Interactions of the Antimalarial Drug Methylene Blue with Methemoglobin and Heme Targets in Plasmodium falciparum: A Physico-Biochemical Study
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DOI：
10.1089/ars.2011.4239
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发表时间：
2012-08-01
影响因子：
6.6
通讯作者：
Elhabiri, Mourad
中科院分区：
文献类型：
--
作者：
Blank, Olga;Davioud-Charvet, Elisabeth;Elhabiri, Mourad
目的：恶性疟原虫对药物的耐药性引起了人们对具有氧化还原活性的亚甲蓝（MB）的新兴趣，迄今为止尚未有耐药性报道。此外，MB 与谷胱甘肽还原酶 (GR) 具有独特的相互作用。然而，MB 与潜在目标的作用/相互作用机制尚未阐明。我们对 MB 和相关含血红素靶标的物理生化研究是在准生理条件下进行的。结果：研究了 Fe(III) 原卟啉二聚体（β-血红素的主要组成部分）的水去质子化。在 pH 6 时，主要的二聚体具有与两种金属配位的水。 pH 值低于 6 时，β-血红素会自发沉淀，这让人想起疟原虫食物液泡中 pH 值 5.0-5.5 时疟原虫色素的生物矿化。 MB 还形成二聚体 (K-Dim = 6800 M-1)，并以 2:1 血红素：MB 夹心复合物 (K-D = 3.16 mu M) 与血红素牢固结合。 GR 催化的 MB 生物活化可有效诱导高铁血红蛋白 (Fe-III) [metHb(Fe-III)] 还原为血红蛋白 (Fe-II)。在与烟酰胺腺嘌呤二核苷酸磷酸系统的 GR/还原形式耦合的测定中，确定了无色亚甲基蓝 (LMB) 介导的还原率 (k(red)(metHb) = 991 M-1.s(-1)）。创新和结论：我们的工作为理解以下方面提供了新的见解：(i) MB 如何与含血红素的靶标相互作用，(ii) 其他相关的 MB 特性，以证实三种主要 LMB 物种作为 pH 函数的分布，以及 (iii) 这种氧化还原活性循环仪如何诱导由氧化还原酶介导的 metHb(Fe-III) 有效催化还原为血红蛋白 (Fe-II)。 MB 的这些物理生化参数为解释疟疾的药理学和病理生理学以及可能的抗疟药物开发新途径开辟了有希望的前景。抗氧化剂。氧化还原信号。 17、544-554。
Aims: Resistance of Plasmodium falciparum to drugs has led to renewed interest of redox-active methylene blue (MB) for which no resistance has been reported so far. Moreover, MB displays unique interactions with glutathione reductase (GR). However, the mechanisms of action/interaction with potential targets of MB are yet to be elucidated. Our physico-biochemical study on MB and relevant hematin-containing targets was performed under quasi-physiological conditions. Results: The water deprotonation of the Fe(III) protoporphyrin dimer, the major building block of beta-hematin, was studied. At pH 6, the predominant dimer possesses water coordinated to both metals. Below pH 6, spontaneous precipitation of beta-hematin occurred reminiscent of hemozoin biomineralization at pH 5.0-5.5 in the food vacuole of the malarial parasite. MB also forms dimers (K-Dim = 6800 M-1) and firmly binds to hematin in a 2: 1 hematin: MB sandwich complex (K-D = 3.16 mu M). MB bioactivation catalyzed by GR induces efficient methemoglobin(Fe-III) [metHb(Fe-III)] reduction to hemoglobin(Fe-II). The reduction rate, mediated by leucomethylene blue (LMB), was determined (k(red)(metHb) = 991 M-1.s(-1)) in an assay coupled to the GR/reduced form of nicotinamide adenine dinucleotide phosphate system. Innovation and Conclusion: Our work provides new insights into the understanding of (i) how MB interacts with hematin-containing targets, (ii) other relevant MB properties in corroboration with the distribution of the three major LMB species as a function of pH, and (iii) how this redox-active cycler induces efficient catalytic reduction of metHb(Fe-III) to hemoglobin(Fe-II) mediated by oxidoreductases. These physico-biochemical parameters of MB open promising perspectives for the interpretation of the pharmacology and pathophysiology of malaria and possibly new routes for antimalarial drug development. Antioxid. Redox Signal. 17, 544-554.