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

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

<i>In-Silico</i> Analysis & <i>In-Vivo</i> Results Concur on Glutathione Depletion in Glyphosate Resistant GMO Soy, Advancing a Systems Biology Framework for Safety Assessment of GMOs

“…In Figure 8, an integrative molecular systems architecture is presented by coupling the dynamics of the molecular interaction in the heretofore known literature, accessible and aggregated by the authors, with the systems architecture of genetic modification, oxidative stress and C1 metabolism derived in earlier work [3]. As shown in Figure 8, glyphosate interacts with C1 metabolism by interfacing through the methionine biosynthesis pathway, which interfaces with both methionine biosynthesis and formaldehyde detoxification path- …”

“…Moreover, the research identified the critical sub-systems of the oxidative stress system, and integrated oxidative stress models with C1 metabolism. Figure 3 shows the computational systems architecture of oxidative stress and C1 metabolism [3]. Interactions of oxidative stress system with C1 metabolism were computationally analyzed to understand the effect of oxidative stress on C1 metabolism.…”

Do GMOs Accumulate Formaldehyde and Disrupt Molecular Systems Equilibria? Systems Biology May Provide Answers

“…This research builds on three recent and specific efforts: 1) a systematic bioinformatics literature review of C1 metabolism [3], 2) in silico modeling of the C1 metabolism system [4], and 3) integrative modeling of oxidative stress and C1 metabolism [5]. A brief review of the results from that previous and recent research [4] [5], is provided below as a contextual basis for the research aim herein.…”

“…A brief review of the results from that previous and recent research [4] [5], is provided below as a contextual basis for the research aim herein. In particular, the review of this research provides the baseline for understanding the temporal dynamics of key biomarkers associated with plant metabolism in non-GMOs.…”

“…The previous work in in silico modeling of C1 metabolism [3]- [5] provides a cogent systems biology framework, which demonstrates that formaldehyde (HCHO) and glutathione (GSH) are two important regulatory molecules involved in the control systems of oxidative stress and C1 Metabolism. The temporal dynamics of formaldehyde and glutathione, in the non-GMO case, will be provided in section 4.2, as a baseline for comparing with the predictions for the GMO case in section 6.0.…”