ArticleBMC bioinformatics2015
Optimal programs of pathway control: dissecting the influence of pathway topology and feedback inhibition on pathway regulation.
Article in BMC bioinformatics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- Applications of artificial intelligence and machine learning in dynamic pathway engineering.Biochemical Society transactions · 2023Review
- Optimal transcriptional regulation of dynamic bacterial responses to sudden drug exposures.Biophysical journal · 2022Article
- Kinetically guided, ratiometric tuning of fatty acid biosynthesis.Metabolic engineering · 2022Review
- Using optimal control to understand complex metabolic pathways.BMC bioinformatics · 2020Article
- Modelling the host-pathogen interactions of macrophages andJournal of the Royal Society, Interface · 2017Article
- Optimality principles reveal a complex interplay of intermediate toxicity and kinetic efficiency in the regulation of prokaryotic metabolism.PLoS computational biology · 2017Article
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Authors and funding
7 authors.
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Abstract
backgroundAdjusting the capacity of metabolic pathways in response to rapidly changing environmental conditions is an important component of microbial adaptation strategies to stochastic environments. In this work, we use advanced dynamic optimization techniques combined with theoretical models to study which reactions in pathways are optimally targeted by regulatory interactions in order to minimize the regulatory effort that is required to adjust the flux through a complex metabolic network. Moreover, we analyze how constraints in the speed at which an organism can respond on a proteomic level influences these optimal targets of pathway control.
resultsWe find that limitations in protein biosynthetic rates have a strong influence. With increasing protein biosynthetic rates the regulatory effort targeting the initial enzyme in a pathway is reduced while the regulatory effort in the terminal enzyme is increased. Studying the impact of allosteric regulation for different pathway topologies, we find that the presence of feedback inhibition by products of metabolic pathways allows organisms to reduce the regulatory effort that is required to control a metabolic pathway in all cases. In a linear pathway this even leads to the case where the sole transcriptional regulatory control of the terminal enzyme is sufficient to control flux through the entire pathway. We confirm the utilization of these pathway regulation strategies through the large-scale analysis of transcriptional regulation in several hundred prokaryotes.
conclusionsThis work expands our knowledge about optimal programs of pathway control. Optimal targets of pathway control strongly depend on the speed at which proteins can be synthesized. Moreover, post-translational regulation such as allosteric regulation allows to strongly reduce the number of transcriptional regulatory interactions required to control a metabolic pathway across different pathway topologies.
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