A Caenorhabditis elegans Genome-Scale Metabolic Network Model

Abstract

Summary Caenorhabditis elegans is a powerful model to study metabolism and how it relates to nutrition, gene expression and life history traits. However, while numerous experimental techniques that enable perturbation of its diet and gene function are available, a high-quality metabolic network model has been lacking. Here, we reconstruct an initial version of the C. elegans metabolic network. This network model contains 1,273 genes, 623 enzymes and 1,985 metabolic reactions and is referred to as iCEL1273. Using flux balance analysis, we show that iCEL1273 is capable of representing the conversion of bacterial biomass into C. elegans biomass during growth, and enables the predictions of gene essentiality and other phenotypes. In addition, we demonstrate that gene expression data can be integrated with the model by comparing metabolic rewiring in dauer animals versus growing larvae. iCEL1273 is available at a dedicated website (www.wormflux.umassmed.edu), and will enable the unraveling of the mechanisms by which different macro- and micronutrients contribute to the animal's physiology.

Metabolic network modeling with model organisms

“…Thus, the nematode is a unique model animal in its suitability for metabolic network modeling and FBA, and a candidate for repeating the success of GSMNMs with microorganisms in an animal model. Two GSMNMs of C. elegans were recently published [57,58] (Table 1). Both models are able to represent growth with the bacterial and axenic diet and involve peculiar traits of C. elegans metabolism known so far, such as the presence of a glyoxylate shunt in an animal and the absence of a de novo NAD biosynthesis pathway.…”

“…The first model in Table 1, iCEL1273 [58], was shown to quantitatively account for the growth of C. elegans at pseudo-steady states in two different stages of life, the L4 growing larvae and egg-laying adults. Gene essentiality for growth at any life stage was systematically analyzed based on assumptions on animal physiology, such as the non-redundant functioning of paralogs in different tissues and the minimization of enzyme usage for an optimal metabolic state (implemented by pFBA).…”

“…iCEL1273 is available at a dedicated website named WormFlux (http://wormflux.umassmed.edu). This webtool is relatively unique because it shows the systematic annotation of all genes in the organism with a pipeline that uses multiple resources [58], and all metabolic reactions used in the reconstruction. Genes, enzymes, metabolites, and pathways are interlinked, searchable, and linked to other databases.…”

Lifespan extension in Caenorhabditis elegans insulin/IGF-1 signalling mutants is supported by non-vertebrate physiological traits

“…Using a recent C. elegans metabolic network model, trehalose production was predicted to be strongly supported by glyoxylate cycle activity under micro-aerobic conditions (Yilmaz & Walhout, 2016). However, in the absence of glyoxylate shunt activity, trehalose can still be produced in lower quantities, probably explaining the partial rescue of icl-1 mutation on daf-2 lifespan extension (Shen et al, 2014).…”

Modelling sponge-symbiont metabolism

“…This analysis presents a significant resource for future GEMs of other sponge-symbiont systems, as biomass compositions of related organisms are frequently used when the specific composition is unknown. To exemplify this point, recently the use of the nucleic acid and amino acid composition of yeast was accepted in the biomass composition of the recent Caenorhabditis elegans GEM (Yilmaz & Walhout, 2016). For organisms which there is little biochemical data, such as growth rates or oxygen consumption, knowing the actual biochemical composition and not using proxy data, ensures that the most significant constraint on network functionality is as accurate as possible (Feist & Palsson, 2010).…”