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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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Response times of the socialist and consumer motifs.The plots show the response time of s as a function of the change in extra-cellular level, Δσ, for both up- and downshifts in σ. The response time is defined as the time required to get to 95% of the final steady state levels of s. For the socialist motif there are two such response times, before (t1) and after (t2) the overshoot (solid lines). The socialist plots also shows the time of peak overshoot (dashed line) and the shaded region defines the duration of the overshoot.
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pone-0004923-g002: Response times of the socialist and consumer motifs.The plots show the response time of s as a function of the change in extra-cellular level, Δσ, for both up- and downshifts in σ. The response time is defined as the time required to get to 95% of the final steady state levels of s. For the socialist motif there are two such response times, before (t1) and after (t2) the overshoot (solid lines). The socialist plots also shows the time of peak overshoot (dashed line) and the shaded region defines the duration of the overshoot.

Mentions: The plots of Fig. 1 show a distinct difference between the socialist and the consumer in the shape of the curves: the socialist has a large overshoot in s levels for both up- and downshifts. Because of the overshoot, the socialist is relatively slow to reach its final steady state, taking around one cell generation (see also Fig. 2). This timescale comes directly from the timescale of degradation of E and T that we set in our equations to be one cell generation. On the other hand, in systems where the initial response is important and not the overshoot, the socialist responds on a timescale much faster than a cell generation for both up- and downshifts in σ.


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

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

Response times of the socialist and consumer motifs.The plots show the response time of s as a function of the change in extra-cellular level, Δσ, for both up- and downshifts in σ. The response time is defined as the time required to get to 95% of the final steady state levels of s. For the socialist motif there are two such response times, before (t1) and after (t2) the overshoot (solid lines). The socialist plots also shows the time of peak overshoot (dashed line) and the shaded region defines the duration of the overshoot.
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Related In: Results  -  Collection

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

pone-0004923-g002: Response times of the socialist and consumer motifs.The plots show the response time of s as a function of the change in extra-cellular level, Δσ, for both up- and downshifts in σ. The response time is defined as the time required to get to 95% of the final steady state levels of s. For the socialist motif there are two such response times, before (t1) and after (t2) the overshoot (solid lines). The socialist plots also shows the time of peak overshoot (dashed line) and the shaded region defines the duration of the overshoot.
Mentions: The plots of Fig. 1 show a distinct difference between the socialist and the consumer in the shape of the curves: the socialist has a large overshoot in s levels for both up- and downshifts. Because of the overshoot, the socialist is relatively slow to reach its final steady state, taking around one cell generation (see also Fig. 2). This timescale comes directly from the timescale of degradation of E and T that we set in our equations to be one cell generation. On the other hand, in systems where the initial response is important and not the overshoot, the socialist responds on a timescale much faster than a cell generation for both up- and downshifts in σ.

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