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

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American Journal of Plant Sciences 2015年第9期6卷 1527-1542页

作者： mrudhuula mohan Santhiya Kothandaram Vyshali Venugopal Prabhakar Deonikar V. A. Shiva Ayyadurai Systems Biology Group International Center for Integrative Systems Cambridge MA USA

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 signifi

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

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<i>In Silico</i>Modeling of C1 Metabolism

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American Journal of Plant Sciences 2015年第9期6卷 1444-1465页

作者： Santhiya Kothandaram Prabhakar Deonikar mrudhuula mohan Vyshali Venugopal V. A. Shiva Ayyadurai Systems Biology Group International Center for Integrative Systems Cambridge MA USA

An integrative computational, in silico, model of C1 metabolism is developed from molecular pathway systems identified from a recent, comprehensive systematic bioinformatics review of C1 metabolism. C1 metabolism is essential for all organisms to provide one-carbon units for methylation and other types of modifications, as well as for nucleic acid, amino acid, and other biomolecule syntheses. C1 metabolism consists of three important molecular pathway systems: 1) methionine biosynthesis, 2) methylation cycle, and 3) formaldehyde detoxification. Each of the three molecular pathway systems is individually modeled using the CytoSolve?? Collaboratory?, a proven and scalable computational systems biology platform for in silico modeling of complex molecular pathway systems. The individual models predict the temporal behavior of formaldehyde, formate, sarcosine, glutathione (GSH), and many other key biomolecules involved in C1 metabolism, which may be hard to measure experimentally. The individual models are then coupled and integrated dynamically using CytoSolve to produce, to the authors’ knowledge, the first comprehensive computational model of C1 metabolism. In silico modeling of the individual and integrated C1 metabolism models enables the identification of the most sensitive parameters involved in the detoxification of formaldehyde. This integrative model of C1 metabolism, giving its systems-based nature, can likely serve as a platform for: 1) generalized research and study of C1 metabolism, 2) hypothesis generation that motivates focused and specific in vitro and in vivo testing in perhaps a more efficient manner, 3) expanding a systems biology understanding of plant bio-molecular systems by integrating other known molecular pathway systems associated with C1 metabolism, and 4) exploring and testing the potential effects of exogenous inputs on the C1 metabolism system.

关键词： In Silico Modeling C1 Metabolism CytoSolve Computational Systems Biology Bioinformatics Molecular Pathway Formaldehyde Detoxification Maize Methionine Biosynthesis Activated Methyl Cycle Folate-Mediated Pathways

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