Discovery of Key Molecular Pathways of C1 Metabolism and Formaldehyde Detoxification in Maize through a Systematic Bioinformatics Literature Review

Abstract

Computational systems biology approaches provide insights to understand complex molecular phenomena in living systems. Such understanding demands the need to systematically interrogate and review existing literature to refine and distil key molecular pathways. This paper explores a methodological process to identify key molecular pathways from systematic bioinformatics literature review. This process is used to identify molecular pathways for a ubiquitous molecular process in all plant biological systems: C1 metabolism and formaldehyde detoxification, specific to maize. The 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. Formaldehyde is a toxic one-carbon molecule which is produced endogenously and found in the environment, and whose detoxification is an important part of C1 metabolism. This systematic review involves a five-part process: 1) framing of the research question; 2) literature collection based on a parallel search strategy; 3) relevant study selection based on search refinement; 4) molecular pathway identification; and 5) integration of key molecular pathway mechanisms to yield a well-defined set molecular systems associated with a particular biochemical function. Findings from this systematic review produced three main molecular systems: a) methionine biosynthesis; b) the methylation cycle; and c) formaldehyde detoxification. Specific insights from the resulting molecular pathways indicate that normal C1 metabolism involves the transfer of a * Corresponding author. P. Deonikar et al.572 carbon group from serine through a folate-mediated pathway to methionine, and eventually the methylation of a biomolecule. In photosynthetic tissues, C1 metabolism often proceeds in reverse towards serine biosynthesis and formate oxidation. C1 metabolism, in maize, appears to be present in the developing embryo and endosperm indicating that these cells are vulnerable to perturbations in formaldehyde detoxification. These insights demonstrate the value of a systematic bioinformatics literature review process from a broad spectrum of domain literature to specific and relevant molecular pathways.

<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

“…A systematic bioinformatics literature review was conducted for the identification of molecular pathways involved in GMO crops, similar to the method used to identify the key molecular pathways of C1 metabolism [1] [2]. Based on the framing of the research question and the application of the search criteria, in Appendix A, through a parallel strategy, the literature collection of an initial set of 242 papers is identified from online databases such as PubMed and Google Scholar.…”

“…In earlier work, spanning four other publications [1]- [4], CytoSolve was used to develop a quantitative molecular systems understanding of C1 metabolism-a critical system of molecular pathways inherent to all plants, fungi and bacteria. The CytoSolve technology (discussed in detail within the Methods section herein) provides a proven and systematic approach to integrate the molecular systems identified in disparate and diverse wet laboratory (in vitro and in vivo) experiments.…”

“…The CytoSolve technology (discussed in detail within the Methods section herein) provides a proven and systematic approach to integrate the molecular systems identified in disparate and diverse wet laboratory (in vitro and in vivo) experiments. In that previous work, molecular pathways identified in 6529 wet laboratory experiments, spanning 184 scientific institutions, across 23 countries were quantitatively integrated using CytoSolve to conclude that the GMO Soy was not substantially equivalent, but materially different, from its non-GMO Soy counterpart, particularly relative to the levels of glutathione (GSH) and formaldehyde (HCHO) within C1 metabolism system [1]- [4].…”

“…C1 metabolism is found in plants, bacteria, yeast, and mammals. 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].…”

C1 Metabolism and Photorespiration of <i>Ficus deltoidea</i> based on Peptide Mass Fingerprinting Approach

“…One-carbon (C1) metabolism is very crucial to provide one carbon for methylation and other types of modifications, as well as for biomolecules such as nucleic acids and amino acids [5]. However, the regulatory mechanism of plant C1 metabolism involving enzymes is not fully understood till to date.…”