Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge 02139, USA.
Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge 02139, USA.
Free Radic Biol Med. 2018 May 20;120:239-245. doi: 10.1016/j.freeradbiomed.2018.03.039. Epub 2018 Mar 22.
Appreciation of peroxiredoxins as the major regulators of HO concentrations in human cells has led to a new understanding of redox signaling. In addition to their status as the primary reducers of HO to water, the oxidized peroxiredoxin byproduct of this reaction has recently been shown capable of participation in HO-mediated signaling pathways through disulfide exchange reactions with the transcription factor STAT3. The dynamics of peroxidase-transcription factor disulfide exchange reactions have not yet been considered in detail with respect to how these reactions fit into the larger network of competing reactions in human cells. In this study, we used a kinetic model of oxidation and reduction reactions related to HO metabolism in the cytosol of human cells to study the dynamics of peroxiredoxin-2 mediated oxidation of the redox-regulated transcription factor STAT3. In combination with previously reported experimental data, the model was used to estimate the rate coefficient of a biomolecular reaction between Prx2 and STAT3 for two sets of assumptions that constitute lower and upper bound cases. Using these estimates, we calculated the relative rates of the reaction of oxidized peroxiredoxin-2 and STAT3 and other competing reactions in the cytosol. These calculations revealed that peroxiredoxin-2-mediated oxidation of STAT3 likely occurs at a much slower rate than competing reactions in the cytosol. This analysis suggests the existence of more complex mechanisms, potentially involving currently unknown protein-protein recognition partners, which facilitate disulfide exchange reactions between peroxiredoxin-2 and STAT3.
对过氧化物酶体增殖物激活受体（peroxiredoxins，简称 Prxs）作为人类细胞中 HO 浓度主要调节剂的认识，导致了对氧化还原信号转导的新理解。除了作为 HO 还原为水的主要还原剂的地位外，最近还表明，该反应的氧化过氧化物酶产物能够通过与转录因子 STAT3 进行二硫键交换反应，参与 HO 介导的信号通路。关于这些反应如何适应人类细胞中竞争反应的更大网络，关于过氧化物酶-转录因子二硫键交换反应的动力学尚未详细考虑。在这项研究中，我们使用了与人类细胞细胞质中 HO 代谢相关的氧化和还原反应的动力学模型，研究了过氧化物酶体 2 介导的氧化还原调节转录因子 STAT3 的动力学。结合先前报道的实验数据，该模型用于估计 Prx2 和 STAT3 之间生物分子反应的速率系数，对于构成下限和上限情况的两组假设。使用这些估计值，我们计算了细胞质中氧化过氧化物酶体 2 和 STAT3 及其他竞争反应的相对反应速率。这些计算表明，过氧化物酶体 2 介导的 STAT3 氧化可能比细胞质中的竞争反应慢得多。这种分析表明存在更复杂的机制，可能涉及当前未知的蛋白质-蛋白质识别伙伴，它们促进了过氧化物酶体 2 和 STAT3 之间的二硫键交换反应。
