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Heme redox potentials hold the key to reactivity differences between nitric oxide reductase and heme-copper oxidase [Biochemistry]
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.4 ) Pub Date : 2018-06-12 , DOI: 10.1073/pnas.1720298115
Ambika Bhagi-Damodaran 1 , Julian H. Reed 2 , Qianhong Zhu 3 , Yelu Shi 4 , Parisa Hosseinzadeh 2 , Braddock A. Sandoval 1 , Kevin A. Harnden 1 , Shuyan Wang 1 , Madeline R. Sponholtz 2 , Evan N. Mirts 5 , Sudharsan Dwaraknath 1 , Yong Zhang 4 , Pierre Moënne-Loccoz 3 , Yi Lu 1, 2, 5
Affiliation  

Despite high structural homology between NO reductases (NORs) and heme-copper oxidases (HCOs), factors governing their reaction specificity remain to be understood. Using a myoglobin-based model of NOR (FeBMb) and tuning its heme redox potentials (E°′) to cover the native NOR range, through manipulating hydrogen bonding to the proximal histidine ligand and replacing heme b with monoformyl (MF-) or diformyl (DF-) hemes, we herein demonstrate that the E°′ holds the key to reactivity differences between NOR and HCO. Detailed electrochemical, kinetic, and vibrational spectroscopic studies, in tandem with density functional theory calculations, demonstrate a strong influence of heme E°′ on NO reduction. Decreasing E°′ from +148 to −130 mV significantly impacts electronic properties of the NOR mimics, resulting in 180- and 633-fold enhancements in NO association and heme-nitrosyl decay rates, respectively. Our results indicate that NORs exhibit finely tuned E°′ that maximizes their enzymatic efficiency and helps achieve a balance between opposite factors: fast NO binding and decay of dinitrosyl species facilitated by low E°′ and fast electron transfer facilitated by high E°′. Only when E°′ is optimally tuned in FeBMb(MF-heme) for NO binding, heme-nitrosyl decay, and electron transfer does the protein achieve multiple (>35) turnovers, previously not achieved by synthetic or enzyme-based NOR models. This also explains a long-standing question in bioenergetics of selective cross-reactivity in HCOs. Only HCOs with heme E°′ in a similar range as NORs (between −59 and 200 mV) exhibit NOR reactivity. Thus, our work demonstrates efficient tuning of E°′ in various metalloproteins for their optimal functionality.



中文翻译:

血红素氧化还原电位是一氧化氮还原酶和血红素铜氧化酶之间反应性差异的关键[生物化学]

尽管NO还原酶(NORs)和血红素铜氧化酶(HCOs)之间具有高度的结构同源性,但控制其反应特异性的因素仍有待了解。使用基于肌红蛋白的NOR模型(Fe B Mb)并通过操纵氢键结合至近端组氨酸配体并取代血红素b来调节其血红素氧化还原电势(E°')以覆盖天然的NOR范围。对于单甲酰基(MF-)或二甲酰基(DF-)血红素,我们在本文中证明E°'是NOR和HCO之间反应性差异的关键。详细的电化学,动力学和振动光谱研究与密度泛函理论计算相结合,证明了血红素E°'对NO还原的强烈影响。E°'从+148降低到-130 mV会显着影响NOR模拟物的电子性能,分别导致NO缔合和血红素亚硝酰衰变速率分别提高180倍和633倍。我们的结果表明,NORs表现出微调的E°',可最大程度地提高其酶促效率,并有助于实现相反因素之间的平衡:低E°'促进NO的快速结合和二亚硝酰基物质的分解,高E°'促进电子的快速转移。只有在铁中优化了E°'的情况下B Mb(MF-血红素)具有NO结合,血红素-亚硝酰基衰变和电子转移的功能,使蛋白质实现了多个(> 35)转换,这是以前合成或基于酶的NOR模型无法实现的。这也解释了HCO中选择性交叉反应的生物能学中一个长期存在的问题。只有血红素E°'与NOR相似的HCO(在-59和200 mV之间)才显示NOR反应性。因此,我们的工作证明了各种金属蛋白中E°'的有效调节可实现其最佳功能。

更新日期:2018-06-13
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