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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12859-015-0587-z) contains supplementary material, which is available to authorized users.
Highlights
Adjusting the capacity of metabolic pathways in response to rapidly changing environmental conditions is an important component of microbial adaptation strategies to stochastic environments
We investigate the influence of protein synthesis rates as well as feedback inhibition on optimal regulatory programs for the control of complex metabolic pathway topologies by means of advanced dynamic optimization techniques
Influence of protein biosynthetic rates on pathway regulation In a previous work we showed that the protein biosynthetic rate of an organism has a strong influence on activation strategies of metabolic pathways [12]
Summary
Adjusting the capacity of metabolic pathways in response to rapidly changing environmental conditions is an important component of microbial adaptation strategies to stochastic environments. Sparse transcriptional regulation, which mostly targets initial and terminal steps of a de Hijas-Liste et al BMC Bioinformatics (2015) 16:163 metabolic pathway, is used for pathways with low protein costs. The existence of these two types of strategies can be explained by a trade-off between the cost of the enzymes catalyzing the reactions of the pathway, that is, the protein cost of the pathway, and response times that can be reduced by an exclusive transcriptional regulation of key steps in a pathway. This trade-off between protein cost and regulation was used to explain the regulation of metabolism in Saccharomyces cerevisiae [14]
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