Abstract
Background/Objectives:The SNF1/AMPK protein kinase has a central role in energy homeostasis in eukaryotic cells. It is activated by energy depletion and stimulates processes leading to the production of ATP while it downregulates ATP-consuming processes. The yeast SNF1 complex is best known for its role in glucose derepression.Methods:We performed a network reconstruction of the Snf1 pathway based on a comprehensive literature review. The network was formalised in the rxncon language, and we used the rxncon toolbox for model validation and gap filling.Results:We present a machine-readable network definition that summarises the mechanistic knowledge of the Snf1 pathway. Furthermore, we used the known input/output relationships in the network to identify and fill gaps in the information transfer through the pathway, to produce a functional network model. Finally, we convert the functional network model into a rule-based model as a proof-of-principle.Conclusions:The workflow presented here enables large scale reconstruction, validation and gap filling of signal transduction networks. It is analogous to but distinct from that established for metabolic networks. We demonstrate the workflow capabilities, and the direct link between the reconstruction and dynamic modelling, with the Snf1 network. This network is a distillation of the knowledge from all previous publications on the Snf1/AMPK pathway. The network is a knowledge resource for modellers and experimentalists alike, and a template for similar efforts in higher eukaryotes. Finally, we envisage the workflow as an instrumental tool for reconstruction of large signalling networks across Eukaryota.
Highlights
The adenosine monophosphate-activated protein kinase (AMPK) is the key regulator of energy homeostasis in eukaryotic cells
We present a network reconstruction of the Snf[1] pathway based on a comprehensive literature review
We examined are directed paths from the inputs to the outputs, indicating that whether the network reconstruction sufficed to enable informathe mechanism of information transfer is understood at the tion transfer through the network as expected
Summary
The adenosine monophosphate-activated protein kinase (AMPK) is the key regulator of energy homeostasis in eukaryotic cells. The Sucrose Non-Fermenting kinase Snf[1] is the AMPK orthologue in baker’s yeast, Saccharomyces cerevisiae.[2] Yeast cells adjust their metabolism in response to nutrient availability to ensure cell survival.[3] Glucose and fructose cause the repression of numerous genes encoding nutrient uptake systems and metabolic enzymes, and cells shifted to less preferred carbon sources change their transcriptome and proteome to utilise new carbon sources.[4] This reprogramming is mediated by the Snf[1] kinase, which is a key regulator of energy metabolism in yeast.[5]. We envisage them as useful tools in yeast Snf1/AMPK research and as templates for similar efforts in higher organisms, and the workflow as a key tool
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