A Genome-Scale Database and Reconstruction of Caenorhabditis elegans Metabolism

Abstract

We present a genome-scale model of Caenorhabditis elegans metabolism along with the public database ElegCyc (http://elegcyc.bioinf.uni-jena.de:1100), which represents a reference for metabolic pathways in the worm and allows for the visualization as well as analysis of omics datasets. Our model reflects the metabolic peculiarities of C. elegans that make it distinct from other higher eukaryotes and mammals, including mice and humans. We experimentally verify one of these peculiarities by showing that the lifespan-extending effect of L-tryptophan supplementation is dose dependent (hormetic). Finally, we show the utility of our model for analyzing omics datasets through predicting changes in amino acid concentrations after genetic perturbations and analyzing metabolic changes during normal aging as well as during two distinct, reactive oxygen species (ROS)-related lifespan-extending treatments. Our analyses reveal a notable similarity in metabolic adaptation between distinct lifespan-extending interventions and point to key pathways affecting lifespan in nematodes.

The genome of Onchocerca volvulus, agent of river blindness

“…By investigating in silico the impact of single reaction knockouts on parasite growth, we identified enzymes likely to be essential to O. volvulus viability. While an ideal method would model the multicellular nature of O. volvulus and treat Wolbachia and Onchocerca metabolisms as two separate compartments with transport processes between them, we believe our approach sets a basis for future methodologies to understanding filarial metabolism and approaches the current state of the art in C. elegans metabolic models 47 . By comparing O. volvulus and L. loa , which does not harbour Wolbachia , we also identified a unique O. volvulus target and those that are compensated by symbiosis.…”

The inducible response of the nematodeCaenorhabditis elegansto members of its natural microbiome across development and adult life

“…In the first step, the procedure uses false discovery rate-adjusted p-values and foldchanges from differential expression analyses of the transcriptomic data to derive for each time point and condition the most likely activity state of a gene. While in the original procedure (Gebauer et al, 2016) this only involved comparisons to adjacent time points, we extended the approach by also comparing, for each time point, gene expression between all conditions. Differential gene expression analysis was performed using DESeq2 with standard parameters (Love et al, 2014).…”

“…We further compared our new data with a recently published proteome analysis of related material (Cassidy et al, 2018), in order to evaluate whether the inducible transcriptome and proteome vary, possibly indicating modifications after gene transcription . We further used the expression data for a reconstruction of the inducible metabolic activities in the worm gut, using the recently established metabolic network for C. elegans (Gebauer et al, 2016).…”

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 second C. elegans GSMNM in Table 1 [57] was also quantitatively challenged, this time using measured amino acid concentrations in wild-type versus perturbed worms. The effect of knocking out bcat-1 , which codes an enzyme responsible for the initial step of branched chain amino acid breakdown, was simulated to indirectly deduce the changes in amino acid levels using FBA, and verified by experimental observations.…”