Genome-scale metabolic network reconstruction of model animals as a platform for translational research

Wang, Hao; Robinson, Jonathan L.; Kocabaş, Pınar; Gustafsson, Johan; Anton, Mihail; Cholley, Pierre-Etienne; Huang, Shan; Gobom, Johan; Svensson, Thomas; Uhlén, Mattias; Zetterberg, Henrik; Nielsen, Jens

doi:10.1073/pnas.2102344118

Cited by 69 publications

(71 citation statements)

References 55 publications

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“…On the other hand, a unified platform of genome-scale metabolic models (GEMs) covering five large model animal models, including mouse ( Mus musculus ), rat ( Rattus norvegicus ), zebrafish ( Danio rerio ), fruit fly ( Drosophila melanogaster ), and worm ( Caenorhabditis elegans ), has recently been introduced. All GEMs can be consulted interactively through the Metabolic Atlas web portal [ 25 ]. We thus have a very comprehensive coverage of metabolic networks in C. elegans by considering both orthologous gene-based pathways and species-specific reactions.…”

Section: The C Elegans Model: Advantages and Limit...mentioning

confidence: 99%

Modeling Alzheimer’s Disease in Caenorhabditis elegans

et al. 2022

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Alzheimer’s disease (AD) is the most frequent cause of dementia. After decades of research, we know the importance of the accumulation of protein aggregates such as β-amyloid peptide and phosphorylated tau. We also know that mutations in certain proteins generate early-onset Alzheimer’s disease (EOAD), and many other genes modulate the disease in its sporadic form. However, the precise molecular mechanisms underlying AD pathology are still unclear. Because of ethical limitations, we need to use animal models to investigate these processes. The nematode Caenorhabditis elegans has received considerable attention in the last 25 years, since the first AD models overexpressing Aβ peptide were described. We review here the main results obtained using this model to study AD. We include works studying the basic molecular mechanisms of the disease, as well as those searching for new therapeutic targets. Although this model also has important limitations, the ability of this nematode to generate knock-out or overexpression models of any gene, single or combined, and to carry out toxicity, recovery or survival studies in short timeframes with many individuals and at low cost is difficult to overcome. We can predict that its use as a model for various diseases will certainly continue to increase.

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Section: The C Elegans Model: Advantages and Limit...mentioning

confidence: 99%

Modeling Alzheimer’s Disease in Caenorhabditis elegans

et al. 2022

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“…Sequence analyses placed two of these candidates – YHR112C and YLL058W - as a part of the PLP-dependent transferase superfamily, together with MET15 and nine other genes primarily involved in sulfur metabolism (Wilson et al, 2009). Of these two genes, YLL058W was the more compelling candidate due to the additional fact that its encoded protein is predicted to have the ability to catalyze homocysteine biosynthesis by a yeast genome-scale metabolic model (Wang et al, 2021).…”

Section: Resultsmentioning

confidence: 99%

On the illusion of auxotrophy:met15Δyeast cells can grow on inorganic sulfur thanks to the previously uncharacterized homocysteine synthase Yll058w

Oss

Parikh

Coelho

et al. 2022

Preprint

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In budding yeast, the Met15 enzyme has long been assumed to be the sole homocysteine synthase, facilitating de novo synthesis of sulfur-containing organic compounds (organosulfurs) from inorganic precursors. Here we show that an alternative homocysteine synthase encoded by the previously uncharacterized gene YLL058W supports growth of mutants lacking MET15 in the absence of exogenous organosulfurs. This growth is observed specifically when cells are deposited in an automated fashion to seed colonies, but not with traditional cell propagation techniques such as thick patches of cells or liquid cultures. We show that the lack of growth in these contexts, which has historically justified the status of MET15 as a classic auxotrophic marker, is largely due to toxic levels of hydrogen sulfide accumulation rather than an inability to perform de novo homocysteine biosynthesis. These data have broad implications for investigations of sulfur starvation/metabolism, including studies of aging and emerging cancer therapeutics.

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“…Assumption 4, where the blood is expected to be constantly replenished with nutrients and thereby have constant metabolite concentrations throughout the tumor, may not hold. Depletion of oxygen in blood vessels is a well-known phenomenon referred to as acute hypoxia (16), and we can assume that the same effect to a certain extent is available for other metabolites. As long as the limiting metabolites are depleted in an equal way that is not a problem.…”

Section: Supplementary Notesmentioning

confidence: 99%

“…Genome-scale modeling (13) of human metabolism involves performing in silico analyses of a reaction network under steady-state conditions and has been used to investigate metabolism in muscles (14), tumor cell lines (15), and Alzheimer’s disease (16), for example. A common method to estimate metabolic fluxes through the network is flux balance analysis (FBA), where the net production or depletion of all internal metabolites is assumed to be zero.…”

Section: Introductionmentioning

confidence: 99%

Metabolic collaboration between cells in the tumor microenvironment has a negligible effect on tumor growth

Gustafsson

Roshanzamir

Hagnestål³

et al. 2022

Preprint

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Metabolism within the tumor microenvironment, where a complex mixture of different cell types resides in a nutrient-deprived surrounding, is not fully understood due to difficulties in measuring metabolic fluxes and exchange of metabolites between different cell types in vivo. Genome-scale metabolic modeling enables estimation of such exchange fluxes as well as an opportunity to gain insight into the metabolic behavior of individual cell types. Here, we estimated the availability of nutrients and oxygen within the tumor microenvironment using concentration measurements from blood together with a metabolite diffusion model. In addition, we developed an approach to efficiently apply enzyme usage constraints in a comprehensive metabolic model of human cells. The combined modeling reproduced severe hypoxic conditions and the Warburg effect, and we found that limitations in enzymatic capacity contribute to cancer cells' preferential use of glutamine as a substrate to the citric acid cycle. Furthermore, we investigated the common belief that some stromal cells are exploited by cancer cells to produce metabolites useful for the cancer cells. We identified a total of 233 potential metabolites that could support collaboration between cancer cells and cancer associated fibroblasts, but when limiting to metabolites previously identified to participate in such collaboration, no growth advantage was observed. Our work highlights the importance of enzymatic capacity limitations for cell behaviors and exemplifies the utility of enzyme constrained models for accurate prediction of metabolism in cells and tumor microenvironments.

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Genome-scale metabolic network reconstruction of model animals as a platform for translational research

Cited by 69 publications

References 55 publications

Modeling Alzheimer’s Disease in Caenorhabditis elegans

Modeling Alzheimer’s Disease in Caenorhabditis elegans

On the illusion of auxotrophy:met15Δyeast cells can grow on inorganic sulfur thanks to the previously uncharacterized homocysteine synthase Yll058w

Metabolic collaboration between cells in the tumor microenvironment has a negligible effect on tumor growth

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