Analysis of the lifetime and spatial localization of hydrogen peroxide generated in the cytosol using a reduced kinetic model |
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| Affiliation: | 1. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA;2. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA;1. Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100193, PR China;2. Shandong University of Traditional Chinese Medicine, Shandong 250355, PR China;1. Department of Biophysics, CIPMM, School of Medicine, Saarland University, Homburg, Germany;2. Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia;1. Department of Pathology, University of Vermont College of Medicine, 149 Beaumont Avenue, Burlington, VT 05405, USA;2. Department of Molecular Physiology and Biophysics, University of Vermont College of Medicine, Burlington, VT 05405, USA;3. Vermont Cancer Center, University of Vermont College of Medicine, Burlington, VT 05405, USA;4. Department of Biochemistry, University of Vermont College of Medicine, Burlington, VT 05405, USA;3. WELBIO, Avenue Hippocrate 75, 1200 Brussels, Belgium,;4. de Duve Institute, Université catholique de Louvain (UCL), Avenue Hippocrate 75, 1200 Brussels, Belgium;;5. Brussels Center for Redox Biology, Avenue Hippocrate 75, 1200 Brussels, Belgium |
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| Abstract: | Hydrogen peroxide (H2O2) acts as a signaling molecule via its reactions with particular cysteine residues of certain proteins. Determining the roles of direct oxidation by H2O2 versus disulfide exchange reactions (i.e. relay reactions) between oxidized and reduced proteins of different identities is a current focus. Here, we use kinetic modeling to estimate the spatial and temporal localization of H2O2 and its most likely oxidation targets during a sudden increase in H2O2 above the basal level in the cytosol. We updated a previous redox kinetic model with recently measured parameters for HeLa cells and used the model to estimate the length and time scales of H2O2 diffusion through the cytosol before it is consumed by reaction. These estimates were on the order of one micron and one millisecond, respectively. We found oxidation of peroxiredoxin by H2O2 to be the dominant reaction in the network and that the overall concentration of reduced peroxiredoxin is not significantly affected by physiological increases in intracellular H2O2 concentration. We used this information to reduce the model from 22 parameters and reactions and 21 species to a single analytical equation with only one dependent variable, i.e. the concentration of H2O2, and reproduced results from the complete model. The reduced kinetic model will facilitate future efforts to progress beyond estimates and precisely quantify how reactions and diffusion jointly influence the distribution of H2O2 within cells. |
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| Keywords: | Hydrogen peroxide Redox signaling Peroxiredoxin Kinetic model Cytosol Endogenous generation |
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