ArticlePLoS biology2008
Dynamics and design principles of a basic regulatory architecture controlling metabolic pathways.
Article in PLoS biology, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 50 citations in OpenAlex.
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- The transcription regulator BrsR serves as a network hub of natural competence protein-protein interactions inProceedings of the National Academy of Sciences of the United States of America · 2021Article
- Dynamic control in metabolic engineering: Theories, tools, and applications.Metabolic engineering · 2021Review
- Metabolite Sequestration Enables Rapid Recovery from Fatty Acid Depletion in Escherichia coli.mBio · 2020Article
- Quantifying Dynamic Regulation in Metabolic Pathways with Nonparametric Flux Inference.Biophysical journal · 2019Article
- Distinct segregation patterns of yeast cell-peripheral proteins uncovered by a method for protein segregatome analysis.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Dynamic metabolic control: towards precision engineering of metabolism.Journal of industrial microbiology & biotechnology · 2018Article
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- Automated optogenetic feedback control for precise and robust regulation of gene expression and cell growth.Nature communications · 2016Article
- Synthetic biology and regulatory networks: where metabolic systems biology meets control engineering.Journal of the Royal Society, Interface · 2016Review
- Regulating ehrlich and demethiolation pathways for alcohols production by the expression of ubiquitin-protein ligase gene HUWE1.Scientific reports · 2016Article
- Mapping eQTL networks with mixed graphical Markov models.Genetics · 2014Article
- Dynamic characterization of growth and gene expression using high-throughput automated flow cytometry.Nature methods · 2014Article
- (Im)Perfect robustness and adaptation of metabolic networks subject to metabolic and gene-expression regulation: marrying control engineering with metabolic control analysis.BMC systems biology · 2013Article
- Engineering dynamic pathway regulation using stress-response promoters.Nature biotechnology · 2013Article
- Regulatory architecture determines optimal regulation of gene expression in metabolic pathways.Proceedings of the National Academy of Sciences of the United States of America · 2012Article
- Comprehensive quantitative analysis of central carbon and amino-acid metabolism in Saccharomyces cerevisiae under multiple conditions by targeted proteomics.Molecular systems biology · 2011Article
- Article
- Selective control of amino acid metabolism by the GCN2 eIF2 kinase pathway in Saccharomyces cerevisiae.BMC biochemistry · 2010Article
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
The dynamic features of a genetic network's response to environmental fluctuations represent essential functional specifications and thus may constrain the possible choices of network architecture and kinetic parameters. To explore the connection between dynamics and network design, we have analyzed a general regulatory architecture that is commonly found in many metabolic pathways. Such architecture is characterized by a dual control mechanism, with end product feedback inhibition and transcriptional regulation mediated by an intermediate metabolite. As a case study, we measured with high temporal resolution the induction profiles of the enzymes in the leucine biosynthetic pathway in response to leucine depletion, using an automated system for monitoring protein expression levels in single cells. All the genes in the pathway are known to be coregulated by the same transcription factors, but we observed drastically different dynamic responses for enzymes upstream and immediately downstream of the key control point-the intermediate metabolite alpha-isopropylmalate (alphaIPM), which couples metabolic activity to transcriptional regulation. Analysis based on genetic perturbations suggests that the observed dynamics are due to differential regulation by the leucine branch-specific transcription factor Leu3, and that the downstream enzymes are strictly controlled and highly expressed only when alphaIPM is available. These observations allow us to build a simplified mathematical model that accounts for the observed dynamics and can correctly predict the pathway's response to new perturbations. Our model also suggests that transient dynamics and steady state can be separately tuned and that the high induction levels of the downstream enzymes are necessary for fast leucine recovery. It is likely that principles emerging from this work can reveal how gene regulation has evolved to optimize performance in other metabolic pathways with similar architecture.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.