Integrative Modeling of Oxidative Stress and C1 Metabolism Reveals Upregulation of Formaldehyde and Downregulation of Glutathione

V. A. Shiva  Ayyadurai; Prabhakar  Deonikar; Vyshali  Venugopal; Santhiya  Kothandaram; Mrudhuula  Mohan

doi:10.4236/ajps.2015.69152

AJPS Vol.6 No.9 , June 2015

Integrative Modeling of Oxidative Stress and C1 Metabolism Reveals Upregulation of Formaldehyde and Downregulation of Glutathione

Mrudhuula Mohan, Santhiya Kothandaram, Vyshali Venugopal, Prabhakar Deonikar, V. A. Shiva Ayyadurai^*

Abstract: This research provides, to the authors’ knowledge, the first integrative model of oxidative stress and C1 metabolism in plants. Increased oxidative stress can cause irreversible damage to photosynthetic components and is harmful to plants. Perturbations at the genetic level may increase oxidative stress and upregulate antioxidant systems in plants. One of the key mechanisms involved in oxidative stress regulation is the ascorbate-glutathione cycle which operates in chloroplasts as well as the mitochondria and is responsible for removal of reactive oxygen species (ROS) generated during photosynthetic operations and respiration. In this research, the complexity of molecular pathway systems of oxidative stress is modeled and then integrated with a previously developed in silico model of C1 metabolism system. This molecular systems integration provides two important results: 1) demonstration of the scalability of the CytoSolve® Collaboratory, a computational systems biology platform that allows for modular integration of molecular pathway models, by coupling the in silico model of oxidative stress with the in silico model of C1 metabolism, and 2) derivation of new insights on the effects of oxidative stress on C1 metabolism relative to formaldehyde (HCHO), a toxic molecule, and glutathione (GSH), an important indicator of oxidative homeostasis in living systems. Previous in silico modeling of C1 metabolism, without oxidative stress, observed complete removal of formaldehyde via formaldehyde detoxification pathway and no change in glutathione concentrations. The results from this research of integrative oxidative stress with C1 metabolism, however, demonstrate significant upregulation of formaldehyde concentrations, with concomitant downregulation and depletion of glutathione. Sensitivity analysis indicates that kGSH-HCHO, the rate constant of GSH-HCHO binding, VSHMT, the rate of formation of sarcosine from glycine, and , the rate of superoxide formation significantly affect formaldehyde homeostasis in the C1 metabolism. Future research may employ this integrative model to explore which conditions initiate oxidative stress and the resultant upregulation and downregulation of formaldehyde and glutathione.

Keywords: C1 Metabolism, Oxidative Stress, Formaldehyde, Glutathione, Formaldehyde Detoxification, Methionine Biosynthesis, Methylation Cycle, Computational Systems Biology, CytoSolve, Systems Integration, Molecular Pathways

Cite this paper: Mohan, M. , Kothandaram, S. , Venugopal, V. , Deonikar, P. and Ayyadurai, V. (2015) Integrative Modeling of Oxidative Stress and C1 Metabolism Reveals Upregulation of Formaldehyde and Downregulation of Glutathione. American Journal of Plant Sciences, 6, 1527-1542. doi: 10.4236/ajps.2015.69152.

References

[1] Demidchic, V. (2015) Mechanisms of Oxidative Stress in Plants: From Classical Chemistry to Cell Biology. Environmental and Experimental Botany, 105, 212-228.
http://dx.doi.org/10.1146/annurev.arplant.50.1.601

[2] Foyer, C.H. and Shigeoka, S. (2011) Understanding Oxidative Stress and Antioxidant Functions to Enhance Photosynthesis. Plant Physiology, 155, 93-100.
http://dx.doi.org/10.1021/bi961235j

[3] Arruda, S.C., Barbosa, H.S., Azevedo, R.A. and Arruda, M.A. (2013) Comparative Studies Focusing on Transgenic Through cp4EPSPS Gene and Non-Transgenic Soybean Plants: An Analysis of Protein Species and Enzymes. Journal of Proteomics, 93, 107-116.
http://dx.doi.org/10.1104/pp.126.1.445

[4] Barbosa, H.S., Arruda, S.C., Azevedo, R.A. and Arruda, M.A. (2012) New Insights on Proteomics of Transgenic Soybean Seeds: Evaluation of Differential Expressions of Enzymes and Proteins. Analytical and Bioanalytical Chemistry, 402. 299-314.
http://dx.doi.org/10.1104/pp.91.3.812

[5] Chew, O., Whelan, J. and Millar, A.H. (2003) Molecular Definition of the Ascorbate-Glutathione Cycle in Arabidopsis mitochondria Reveals Dual Targeting of Antioxidant Defenses in Plants. Journal of Biological Chemistry, 278, 46869-46877.
http://dx.doi.org/10.1016/S0891-5849(96)00185-2

[6] Ayyadurai, V.A. and Dewey, C.F. (2011) CytoSolve: A Scalable Computational Method for Dynamic Integration of Multiple Molecular Pathway Models. Cellular and Molecular Bioengineering, 4, 28-45.
http://dx.doi.org/10.1007/s12195-010-0143-x

[7] Deonikar, P., Kothandaram, S., Mohan, M., Kollin, C., Konecky, P., Olovyanniko, R., Zamore, Z., Carey, B. and Ayyadurai1, V.A.S. (2015) Discovery of Key Molecular Pathways of C1 Metabolism and Formaldehyde Detoxification in Maize through a Systematic Bioinformatics Literature Review. Agricultural Sciences, 6, 571-585.
http://dx.doi.org/10.4236/as.2015.65056

[8] Kothandaram, S., Deonikar, P., Mohan, M., Venugopal, V. and Ayyadurai, V.A.S. (2015) In Silico Modeling of C1 Metabolism. American Journal of Plant Sciences. [In Press]
http://dx.doi.org/10.1016/B978-0-12-681903-8.50011-4

[9] Babbs, C.F. and Steiner, M.G. (1990) Simulation of Free Radical Reactions in Biology and Medicine: A New Two-Compartment Kinetic Model of Intracellular Lipid Peroxidation. Free Radical Biology and Medicine, 8, 471-485.
http://dx.doi.org/10.1016/0891-5849(90)90060-V

[10] Polle, A. (2001) Dissecting the Superoxide Dismutase-Ascorbate-Glutathione-Pathway in Chloroplasts by Metabolic Modeling. Computer Simulations as a Step towards Flux Analysis. Plant Physiology, 126, 445-462.
http://dx.doi.org/10.1104/pp.126.1.445

[11] Henle, E.S., Luo, Y. and Linn, S. (1996) Fe2+, Fe3+, and Oxygen React with DNA-Derived Radicals Formed during Iron-Mediated Fenton Reactions. Biochemistry, 35, 12212-12219.
http://dx.doi.org/10.1021/bi961235j

[12] Mano, J. (2012) Reactive Carbonyl Species: Their Production from Lipid Peroxides, Action in Environmental Stress, and the Detoxification Mechanism. Plant Physiology and Biochemistry, 59, 90-97.
http://dx.doi.org/10.1016/j.plaphy.2012.03.010

[13] Yokota, A., Kitaoka, S., Miura, K. and Wadano, A. (1985) Reactivity of Glyoxylate with Hydrogen Perioxide and Simulation of the Glycolate Pathway of C3 Plants and Euglena. Planta, 165, 59-67.
http://dx.doi.org/10.1007/BF00392212

[14] Buettner, G.R., Ng, C.F., Wang, M., Rodgers, V.G. and Schafer, F.Q. (2006) A New Paradigm: Manganese Superoxide Dismutase Influences the Production of H2O2 in Cells and Thereby Their Biological State. Free Radical Biology and Medicine, 41, 1338-1350.
http://dx.doi.org/10.1016/j.freeradbiomed.2006.07.015

[15] Wlodek, L. (1988) The Reaction of Sulfhydryl Groups with Carbonyl Compounds. Acta Biochimica Polonica, 35, 307-317.

[16] Havir, E.A. and McHale, N.A. (1989) Enhanced-Peroxidatic Activity in Specific Catalase Isozymes of Tobacco, Barley, and Maize. Plant Physiology, 91, 812-815.
http://dx.doi.org/10.1104/pp.91.3.812

[17] Achkor, H., et al. (2003) Enhanced Formaldehyde Detoxification by Overexpression of Glutathione-Dependent Formaldehyde Dehydrogenase from Arabidopsis. Plant Physiology, 132, 2248-2255.
http://dx.doi.org/10.1104/pp.103.022277

[18] Goyer, A., et al. (2004) Characterization and Metabolic Function of a Peroxisomal Sarcosine and Pipecolate Oxidase from Arabidopsis. Journal of Biological Chemistry, 279, 16947-16953.
http://dx.doi.org/10.1074/jbc.M400071200