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

Abstract

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.

<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 this initial work [1] three critical molecular systems involved in C1 metabolism were identified as shown in Figure 1. Such identification provided the basis for the development of an initial in silico computational model that integrates these three systems of C1 metabolism [2].…”

“…That initial work resulted in a computational model, which, to the best of our knowledge, is the first computational model to predict the interrelationships of the various molecular species across the three biochemical processes of C1 metabolism: methionine biosynthesis, activated methyl cycle and formaldehyde detoxification [2]. The individual models of C1 metabolism predict temporal behavior of key molecules in C1 metabolism such as formaldehyde (HCHO), formate, sarcosine and glutathione (GSH).…”

“…The individual models of C1 metabolism predict temporal behavior of key molecules in C1 metabolism such as formaldehyde (HCHO), formate, sarcosine and glutathione (GSH). The integrated model of C1 metabolism predicts that glutathione levels are minimally affected and maintain a steady state and formaldehyde is evanescently produced and detoxified rapidly [2].…”

“…In subsequent research, while the initial model of C1 metabolism provided important insights, other exogenous molecular systems affecting C1 metabolism were also identified, from using and combining the results from other scientific literature [2]. C1 metabolism from a systems perspective is not an isolated system.…”

“…In that research, a systems architecture map, as shown in Figure 2, was developed to provide a blueprint for modular integration of other systems to evolve and advance the C1 metabolism model. Such exogenous systems include: tetrahydrofolate (THF) biosynthesis, oxidative stress metabolism, catalase activity, shikimic acid metabolism, adenosine metabolism, glyphosate metabolism, formate biosynthesis, and serine biosynthesis, for example [2]. Moreover, the research identified the critical sub-systems of the oxidative stress system, and integrated oxidative stress models with C1 metabolism.…”