Abstract
Temporal changes of gene expression are a well-known regulatory feature of all cells, which is commonly perceived as a strategy to adapt the proteome to varying external conditions. However, temporal (rhythmic and non-rhythmic) changes of gene expression are also observed under virtually constant external conditions. Here we hypothesize that such changes are a means to render the synthesis of the metabolic output more efficient than under conditions of constant gene activities. In order to substantiate this hypothesis, we used a flux-balance model of the cellular metabolism. The total time span spent on the production of a given set of target metabolites was split into a series of shorter time intervals (metabolic phases) during which only selected groups of metabolic genes are active. The related flux distributions were calculated under the constraint that genes can be either active or inactive whereby the amount of protein related to an active gene is only controlled by the number of active genes: the lower the number of active genes the more protein can be allocated to the enzymes carrying non-zero fluxes. This concept of a predominantly protein-limited efficiency of gene expression clearly differs from other concepts resting on the assumption of an optimal gene regulation capable of allocating to all enzymes and transporters just that fraction of protein necessary to prevent rate limitation. Applying this concept to a simplified metabolic network of the central carbon metabolism with glucose or lactate as alternative substrates, we demonstrate that switching between optimally chosen stationary flux modes comprising different sets of active genes allows producing a demanded amount of target metabolites in a significantly shorter time than by a single optimal flux mode at fixed gene activities. Our model-based findings suggest that temporal expression of metabolic genes can be advantageous even under conditions of constant external substrate supply.
Highlights
The cellular metabolism represents a network of thousands of chemical reactions and transport processes, most of them catalyzed by specific enzymes and transport proteins
Applying this concept to a simplified metabolic network of the central carbon metabolism with glucose or lactate as alternative substrates, we demonstrate that switching between optimally chosen stationary flux modes comprising different sets of active genes allows producing a demanded amount of target metabolites in a significantly shorter time than by a single optimal flux mode at fixed gene activities
In order to assess whether successive switching between different minimal gene sets (MGS) leads to a decrease of the total production time required for the accomplishment of the metabolic output, we introduce the gain
Summary
The cellular metabolism represents a network of thousands of chemical reactions and transport processes, most of them catalyzed by specific enzymes and transport proteins. The most important feature of the cellular metabolic network is its ability to adjust the metabolic output to varying external conditions as, for example, an increase in the concentration of pro-inflammatory cytokines or growth factors, depletion of specific substrates (in particular oxygen) or challenges by toxic compounds. This adjustment of the metabolic network to alterations in the external conditions is achieved by selectively increasing or decreasing the capacity of enzymes and membrane transporters. Long-term changes of enzyme activities on a time scale of minutes, hours and even days result from changes in the expression of enzymes, brought about by changes of the rate of transcription (DNA to mRNA), translation (mRNA to protein) and proteolysis (protein to amino acids)
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