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

Abstract

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. © 2017 Wiley Periodicals, Inc. How to cite this article:WIREs Syst Biol Med 2018, 10:e1396. doi: 10.1002/wsbm.1396 INTRODUCTIONT he function and structure of metabolic and transcriptional networks are well characterized. Transcription is the first step in the control of gene expression. Metabolism governs the supply of energy and cellular building blocks. Besides regulatory interactions within each of the two networks, mutual feedback is abundant between them. Already in the 1950s the discovery of the lac operon showed that transcription impacts metabolic operation (metabolic gene expression).1 A few years later, the discovery of allosteric metabolite-protein interactions provided a mechanism for metabolitedriven transcription (metabolic feedback on transcription).2 In our view, the crosstalk between metabolism and transcription results from two interdependent processes: information from transcriptional networks to metabolism is transmitted by metabolic gene expression, while metabolic information is conveyed via metabolic feedback on transcription (Figure 1). In the past decade, systems biology has mostly been focused on genomes, transcriptomes, and proteomes owing to the availability of advanced and sensitive technologies. Recent improvements in metabolomics methods 3 have now enabled metabolites to become the focus of many studies. [4][5][6][7] The fundamental challenge for understanding how metabolites regulate transcriptional programs lies in identifying metabolites that are key signals for transcriptional regulators. This is illustrated by the fact that the master regulatory metabolite of catabolic genes in Escherichia coli-α-ketoglutarate-was identified only recently, 8 although the regulatory mechanism has been known since the early 1950s (carbon catabolite repression). Recent findings suggest that such metabolic feedback on transcription could of 11govern global gene regulation and metabolism. For example, a recent study in yea...

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