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The impact of electrostatics in redox modulation of oxidative stress by Mn porphyrins: Protection of SOD-deficient E. coli via alternative mechanism where Mn porphyrin acts as a Mn-carrier

机译：静电对锰卟啉对氧化应激的氧化还原调节的影响：通过替代机制（其中锰卟啉充当锰载体）保护SOD缺陷型大肠杆菌

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Understanding the factors that determine the ability of Mn porphyrins to scavenge reactive species is essential for tuning their in vivo efficacy. We present herein the revised structure-activity relationships accounting for the critical importance of electrostatics in the Mn porphyrin-based redox modulation systems and show that the design of effective SOD mimics (per se) based on anionic porphyrins is greatly hindered by inappropriate electrostatics. A new strategy for the β-octabromination of the prototypical anionic Mn porphyrins Mn(III) meso-tetrakis(p-carboxylatophenyl)porphyrin ([MnIIITCPP]3− or MnTBAP3−) and Mn(III) meso-tetrakis(p-sulfonatophenyl)porphyrin ([MnIIITSPP]3−), to yield the corresponding anionic analogues [MnIIIBr8TCPP]3− and [MnIIIBr8TSPP]3−, respectively, is described along with characterization data, stability studies, and their ability to substitute for SOD in SOD-deficient E. coli. Despite the MnIII/MnII reduction potential of [MnIIIBr8TCPP]3− and [MnIIIBr8TSPP]3− being close to the SOD-enzyme optimum and nearly identical to that of the cationic Mn(III) meso-tetrakis(N-methylpyridinium-2-yl)porphyrin (MnIIITM-2-PyP5+), the SOD activity of both anionic brominated porphyrins ([MnIIIBr8TCPP]3−, E½ = +213 mV vs NHE, log kcat = 5.07; [MnIIIBr8TSPP]3−, E½ = +209 mV, log kcat = 5.56) is considerably lower than that of MnIIITM-2-PyP5+ (E½ = +220 mV, log kcat = 7.79). This illustrates the impact of electrostatic guidance of O2•− toward the metal center of the mimic. With low kcat, the [MnIIITCPP]3−, [MnIIITSPP]3−, and [MnIIIBr8TCPP]3− did not rescue SOD-deficient E. coli. The striking ability of [MnIIIBr8TSPP]3− to substitute for the SOD enzymes in the E. coli model does not correlate with its log kcat. In fact, the protectiveness of [MnIIIBr8TSPP]3− is comparable to or better than that of the potent SOD mimic MnIIITM-2-PyP5+, even though the dismutation rate constant of anionic complex is 170-fold smaller. Analyses of the medium and E. coli cell extract revealed that the major species in the [MnIIIBr8TSPP]3− system is not the Mn complex, but the free-base porphyrin [H2Br8TSPP]4− instead. Control experiments with extracellular MnCl2 showed lack of E. coli protection, indicating that “free” Mn2+ cannot enter the cell at significant extent. We proposed herein the alternative mechanism where a labile Mn porphyrin [MnIIIBr8TSPP]3− is not a SOD mimic per se but carries Mn into the E. coli cell.
机译：了解决定锰卟啉清除反应性能力的因素对于调节其体内功效至关重要。我们在本文中提出了修正的结构-活性关系，这说明了静电在Mn卟啉氧化还原调节系统中至关重要，并表明基于阴离子卟啉的有效SOD模拟物（本身）的设计受到不适当静电的极大阻碍。典型的阴离子锰卟啉Mn（III）中四（对羧基苯基苯基）卟啉（[Mn III TCPP] 3 − 或MnTBAP 3 − ）和Mn（III）中四（对-磺基苯基）卟啉（[Mn III TSPP] 3-）分别产生相应的阴离子类似物[Mn III Br8TCPP] 3-和[Mn III Br8TSPP] 3-连同特性数据，稳定性研究及其在SOD缺陷型大肠杆菌中替代SOD的能力一起进行了描述。尽管[Mn III Br8TCPP] 3-和[Mn 的Mn III / Mn II 还原电位> III Br8TSPP] 3-接近SOD最佳酶，与阳离子Mn（III）中四（N-甲基吡啶-2-基）卟啉几乎相同（Mn III TM-2-PyP 5 + ），两种阴离子溴化卟啉（[Mn III Br8TCPP] 3 − ，E½= +213 mV，相对于NHE，log kcat = 5.07； [Mn III Br8TSPP] 3 − ，E½= +209 mV，log kcat = 5.56）大大低于Mn III TM-2-PyP 5 + （E½= +220 mV，log kcat = 7.79）。这说明了O2 •-的静电引导朝向模拟物金属中心的影响。在低kcat的情况下，[Mn III TCPP] 3-，[Mn III TSPP] 3-和[Mn III Br8TCPP] 3-无法挽救SOD缺陷型大肠杆菌。大肠杆菌模型中[Mn III Br8TSPP] 3-替代SOD酶的打击能力与其log k cat 不相关。子>。实际上，[Mn III Br 8 TSPP] 3-的保护性与有效的SOD模拟Mn < sup> III TM-2-PyP 5 + ，即使阴离子络合物的歧化速率常数小170倍。培养基和大肠杆菌细胞提取物的分析表明，[Mn III Br 8 TSPP] 3-系统中的主要种类不是Mn络合物，但是游离碱卟啉[H 2 Br 8 TSPP] 4-代替。用细胞外MnCl 2 进行的对照实验显示缺乏大肠杆菌保护，这表明“游离” Mn 2 + 不能大量进入细胞。我们在这里提出了另一种机制，其中不稳定的锰卟啉[Mn III Br 8 TSPP] 3-本身不是SOD模拟物，但带有锰进入大肠杆菌细胞。

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