Potential role of tryptophan and chloride in the inhibition of human myeloperoxidase
Potential role of tryptophan and chloride in the inhibition of human myeloperoxidase
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DOI：
10.1016/j.freeradbiomed.2008.01.003
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发表时间：
2008-04-15
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：
Galijasevic, Semira;Abdulhamid, Ibrahim;Abu-Soud, Husam M.
髓过氧化物酶（MPO）在存在和不存在氯离子（Cl-）的情况下结合H2 O2，并通过1 e（-）和2 e（-）氧化途径催化形成强氧化剂。这些强氧化剂与多种疾病的发病机制有关，包括动脉粥样硬化、哮喘、关节炎和癌症。因此，MPO及其副产物的抑制可能在生物系统中具有广泛的应用。使用直接快速动力学测量和H2 O2选择性电极，我们表明，色氨酸（Trp），一种必需的氨基酸，连接在动力学上的MPO催化在生理条件下的抑制。在不存在和存在血浆水平的Cl-的情况下，Trp通过与MPO结合，形成无活性复合物Trp-MPO和Trp-MPO-Cl，并加速MPO化合物II（MPO的无活性形式）的形成，在不同程度上灭活MPO。MPO的失活反映为MPO-Fe（III）直接转化为MPO化合物II，而没有任何化合物I积累的迹象。这种行为表明，色氨酸结合调节MPO中间体的形成和它们的衰减速率。重要的是，Trp是MPO化合物II的不良底物，并且在使复合物形成不稳定中没有作用。因此，总MPO催化活性将受到以下限制：（1）Trp从Trp-MPO和Tip-MPO-Cl复合物中解离，（2）MPO化合物I相对于Trp对Cl-的亲和力，和（3）MPO化合物II向MPO-Fe（III）的缓慢转化。重要的是，MPO的色氨酸依赖性抑制发生在跨越各种生理和补充范围的广泛浓度范围内。(c)2008年爱思唯尔公司All rights reserved.
Myeloperoxidase (MPO) binds H2O2 in the absence and presence of chloride (Cl-) and catalyzes the formation of potent oxidants through 1e(-) and 2e(-) oxidation pathways. These potent oxidants have been implicated in the pathogenesis of various diseases including atherosclerosis, asthma, arthritis, and cancer. Thus, inhibition of MPO and its by-products may have a wide application in biological systems. Using direct rapid kinetic measurements and H2O2-selective electrodes, we show that tryptophan (Trp), an essential amino acid, is linked kinetically to the inhibition of MPO catalysis under physiological conditions. Trp inactivated MPO in the absence and presence of plasma levels of Cl-, to various degrees, through binding to MPO, forming the inactive complexes Trp-MPO and Trp-MPO-Cl, and accelerating formation of MPO Compound II, an inactive form of MPO. Inactivation of MPO was mirrored by the direct conversion of MPO-Fe(III) to MPO Compound II without any sign of Compound I accumulation. This behavior indicates that Trp binding modulates the formation of MPO intermediates and their decay rates. Importantly, Trp is a poor substrate for MPO Compound II and has no role in destabilizing complex formation. Thus, the overall MPO catalytic activity will be limited by: (1) the dissociation of Trp from Trp-MPO and Tip-MPO-Cl complexes, (2) the affinity of MPO Compound I toward Cl- versus Trp, and (3) the slow conversion of MPO Compound II to MPO-Fe(III). Importantly, Trp-dependent inhibition of MPO occurred at a wide range of concentrations that span various physiological and supplemental ranges. (c) 2008 Elsevier Inc. All rights reserved.