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Dynamics of uptake and metabolism of small molecules in cellular response systems.

Werner M, Semsey S, Sneppen K, Krishna S - PLoS ONE (2009)

Bottom Line: Our analysis emphasizes the core of the regulation found in many motifs at the interface between the metabolic network and the environment of the cell.By simplifying the regulation into uptake and the first metabolic step, we provide a basis for elaborate studies of more realistic network structures.Particularly, this theoretical analysis predicts that FeS cluster formation plays an important role in the dynamics of iron homeostasis.

View Article: PubMed Central - PubMed

Affiliation: Department of Computational Biology, Royal Institute of Technology, Albanova University Center, Stockholm, Sweden. mariawer@kth.se

ABSTRACT

Background: Proper cellular function requires uptake of small molecules from the environment. In response to changes in extracellular conditions cells alter the import and utilization of small molecules. For a wide variety of small molecules the cellular response is regulated by a network motif that combines two feedback loops, one which regulates the transport and the other which regulates the subsequent metabolism.

Results: We analyze the dynamic behavior of two widespread but logically distinct two-loop motifs. These motifs differ in the logic of the feedback loop regulating the uptake of the small molecule. Our aim is to examine the qualitative features of the dynamics of these two classes of feedback motifs. We find that the negative feedback to transport is accompanied by overshoot in the intracellular amount of small molecules, whereas a positive feedback to transport removes overshoot by boosting the final steady state level. On the other hand, the negative feedback allows for a rapid initial response, whereas the positive feedback is slower. We also illustrate how the dynamical deficiencies of one feedback motif can be mitigated by an additional loop, while maintaining the original steady-state properties.

Conclusions: Our analysis emphasizes the core of the regulation found in many motifs at the interface between the metabolic network and the environment of the cell. By simplifying the regulation into uptake and the first metabolic step, we provide a basis for elaborate studies of more realistic network structures. Particularly, this theoretical analysis predicts that FeS cluster formation plays an important role in the dynamics of iron homeostasis.

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Dynamics of the socialist and consumer motifs.The left column of plots show the dynamics of intracellular s levels, as a function of time, for the corresponding motifs, for four different up-shifts in extracellular levels from σ to σ+Δσ with Δσ = 10, 102, 103 and 104. The starting value is σ = 1. The right column shows similar dynamics of s for downshifts: Δ σ = −9000, −9900, −9990 and −9999. The starting value is σ = 104. Time is measured in units of one cell generation.
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pone-0004923-g001: Dynamics of the socialist and consumer motifs.The left column of plots show the dynamics of intracellular s levels, as a function of time, for the corresponding motifs, for four different up-shifts in extracellular levels from σ to σ+Δσ with Δσ = 10, 102, 103 and 104. The starting value is σ = 1. The right column shows similar dynamics of s for downshifts: Δ σ = −9000, −9900, −9990 and −9999. The starting value is σ = 104. Time is measured in units of one cell generation.

Mentions: We examine the qualitative dynamical behaviour of regulatory motifs consisting of two entangled feedback loops where a single regulator controls both the uptake (influx) and metabolism (out-flux) of a small molecule. The logically distinct combinations of two feedback loops, shown in Fig. 1, suit the requirements for regulation of different classes of small molecules, and are found, respectively, in networks regulating the response to necessary but potentially toxic molecules (e.g. Fe, Zn), and in different sugar networks (e.g. lactose, galactose). We call the motif found in metal ion regulation systems the socialist motif, and the one found in sugar response systems the consumer motif. The names originate from our previous study of the steady-state properties of these motifs [2]: the socialist motif is so named because it tightly constrains the steady-state intracellular small molecule concentration, while the consumer results in a sharp increase of transport and consumption when the small molecule is present extracellularly.


Dynamics of uptake and metabolism of small molecules in cellular response systems.

Werner M, Semsey S, Sneppen K, Krishna S - PLoS ONE (2009)

Dynamics of the socialist and consumer motifs.The left column of plots show the dynamics of intracellular s levels, as a function of time, for the corresponding motifs, for four different up-shifts in extracellular levels from σ to σ+Δσ with Δσ = 10, 102, 103 and 104. The starting value is σ = 1. The right column shows similar dynamics of s for downshifts: Δ σ = −9000, −9900, −9990 and −9999. The starting value is σ = 104. Time is measured in units of one cell generation.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2654506&req=5

pone-0004923-g001: Dynamics of the socialist and consumer motifs.The left column of plots show the dynamics of intracellular s levels, as a function of time, for the corresponding motifs, for four different up-shifts in extracellular levels from σ to σ+Δσ with Δσ = 10, 102, 103 and 104. The starting value is σ = 1. The right column shows similar dynamics of s for downshifts: Δ σ = −9000, −9900, −9990 and −9999. The starting value is σ = 104. Time is measured in units of one cell generation.
Mentions: We examine the qualitative dynamical behaviour of regulatory motifs consisting of two entangled feedback loops where a single regulator controls both the uptake (influx) and metabolism (out-flux) of a small molecule. The logically distinct combinations of two feedback loops, shown in Fig. 1, suit the requirements for regulation of different classes of small molecules, and are found, respectively, in networks regulating the response to necessary but potentially toxic molecules (e.g. Fe, Zn), and in different sugar networks (e.g. lactose, galactose). We call the motif found in metal ion regulation systems the socialist motif, and the one found in sugar response systems the consumer motif. The names originate from our previous study of the steady-state properties of these motifs [2]: the socialist motif is so named because it tightly constrains the steady-state intracellular small molecule concentration, while the consumer results in a sharp increase of transport and consumption when the small molecule is present extracellularly.

Bottom Line: Our analysis emphasizes the core of the regulation found in many motifs at the interface between the metabolic network and the environment of the cell.By simplifying the regulation into uptake and the first metabolic step, we provide a basis for elaborate studies of more realistic network structures.Particularly, this theoretical analysis predicts that FeS cluster formation plays an important role in the dynamics of iron homeostasis.

View Article: PubMed Central - PubMed

Affiliation: Department of Computational Biology, Royal Institute of Technology, Albanova University Center, Stockholm, Sweden. mariawer@kth.se

ABSTRACT

Background: Proper cellular function requires uptake of small molecules from the environment. In response to changes in extracellular conditions cells alter the import and utilization of small molecules. For a wide variety of small molecules the cellular response is regulated by a network motif that combines two feedback loops, one which regulates the transport and the other which regulates the subsequent metabolism.

Results: We analyze the dynamic behavior of two widespread but logically distinct two-loop motifs. These motifs differ in the logic of the feedback loop regulating the uptake of the small molecule. Our aim is to examine the qualitative features of the dynamics of these two classes of feedback motifs. We find that the negative feedback to transport is accompanied by overshoot in the intracellular amount of small molecules, whereas a positive feedback to transport removes overshoot by boosting the final steady state level. On the other hand, the negative feedback allows for a rapid initial response, whereas the positive feedback is slower. We also illustrate how the dynamical deficiencies of one feedback motif can be mitigated by an additional loop, while maintaining the original steady-state properties.

Conclusions: Our analysis emphasizes the core of the regulation found in many motifs at the interface between the metabolic network and the environment of the cell. By simplifying the regulation into uptake and the first metabolic step, we provide a basis for elaborate studies of more realistic network structures. Particularly, this theoretical analysis predicts that FeS cluster formation plays an important role in the dynamics of iron homeostasis.

Show MeSH
Related in: MedlinePlus