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Crosstalk between transcription and metabolism: how much enzyme is enough for a cell?

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Cells employ various mechanisms for dynamic control of enzyme expression. An important mechanism is mutual feedback—or crosstalk—between transcription and metabolism. As recently suggested, enzyme levels are often much higher than absolutely needed to maintain metabolic flux. However, given the potential burden of high enzyme levels it seems likely that cells control enzyme expression to meet other cellular objectives. In this review, we discuss whether crosstalk between metabolism and transcription could inform cells about how much enzyme is optimal for various fitness aspects. Two major problems should be addressed in order to understand optimization of enzyme levels by crosstalk. First, mapping of metabolite–protein interactions will be crucial to obtain a better mechanistic understanding of crosstalk. Second, investigating cellular objectives that define optimal enzyme levels can reveal the functional relevance of crosstalk. We present recent studies that approach these problems, drawing from experimental transcript and metabolite data, and from theoretical network analyses.

Schematic of the cellular processes that are involved in crosstalk between transcription and metabolism. Metabolic gene expression represents transcription and translation of a gene into a metabolic enzyme. Each enzyme catalyzes a certain reaction within the metabolic pathway (enzyme catalysis). Metabolic homeostasis implies that reaction rates A, B, and C are equal, that is, metabolite concentrations are constant and metabolic flux through the pathway is constant. Metabolites can interact with transcriptional regulatory proteins and modulate their activity (metabolic feedback on transcription). The example here shows an inhibition of a transcription factor (TF) by metabolite 4. The transcription rates of genes A, B, and C are then regulated by the activity of the transcription factor (transcription regulation).
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Robust versus efficient enzyme levels. (a) Enzymes in the metabolic pathway are overabundant and not operating at their full catalytic potential. The size of the enzyme indicates abundance and the blue fill activity. For example, enzyme B operates at half‐maximal velocity (vmax). Perturbations can be compensated without regulating enzyme abundance by transcription (e.g., changing substrate concentrations). (b) Enzymes in the metabolic pathway are expressed at the minimum level that allows the same metabolic flux as in (a). All enzymes operate at their full catalytic potential (vmax) and are saturated with substrates (the size of metabolites indicates the concentration). Decreasing a single enzyme level results in a metabolic bottleneck and in flux limitations. Transcriptional feedback regulation can compensate such perturbations, but slower than in (a).
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Laboratory Methods and Technologies > Metabolomics
Biological Mechanisms > Metabolism
Biological Mechanisms > Regulatory Biology

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In the Spotlight

Jens Nielsen

Jens Nielsen
is a Professor in the Department of Biology and Biological Engineering at Chalmers University of Technology in Göteborg, Sweden. His research focus is on systems biology of metabolism. The yeast Saccharomyces cerevisiae is the lab’s key organism for experimental research, but they also work with Aspergilli oryzae.

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