Global coordination of metabolic pathways in Escherichia coli by active and passive regulation. Issue 4 (14th April 2021)

• Record Type: Journal Article
• Authors: Kochanowski, Karl; Okano, Hiroyuki; Patsalo, Vadim; Williamson, James; Sauer, Uwe; Hwa, Terence
• Is Part Of: Molecular systems biology. Volume 17:Issue 4(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-04-14
• Subjects: 13C flux analysis -- Crp -- metabolomics -- proteomics -- regulation analysis; Molecular biology -- Periodicals; Systems biology -- Periodicals; 572.8
• DOI: 10.15252/msb.202010064
• Languages: English
• ISSNs: 1744-4292

Abstract

Abstract: Microorganisms adjust metabolic activity to cope with diverse environments. While many studies have provided insights into how individual pathways are regulated, the mechanisms that give rise to coordinated metabolic responses are poorly understood. Here, we identify the regulatory mechanisms that coordinate catabolism and anabolism in Escherichia coli . Integrating protein, metabolite, and flux changes in genetically implemented catabolic or anabolic limitations, we show that combined global and local mechanisms coordinate the response to metabolic limitations. To allocate proteomic resources between catabolism and anabolism, E . coli uses a simple global gene regulatory program. Surprisingly, this program is largely implemented by a single transcription factor, Crp, which directly activates the expression of catabolic enzymes and indirectly reduces the expression of anabolic enzymes by passively sequestering cellular resources needed for their synthesis. However, metabolic fluxes are not controlled by this regulatory program alone; instead, fluxes are adjusted mostly through passive changes in the local metabolite concentrations. These mechanisms constitute a simple but effective global regulatory program that coarsely partitions resources between different parts of metabolism while ensuring robust coordination of individual metabolic reactions. Synopsis: The transcription factor Crp coordinates E. coli 's response to metabolic limitations by directly and indirectly regulating catabolic and anabolic enzyme expression. This regulatory program is adjusted locally through passive changes in metabolite concentrations. Multi‐omics characterization of E. coli 's response to genetically implemented metabolic limitations reveals coordination mechanisms between catabolism and anabolism. The transcription factor Crp enables coordinated proteome response by directly activating catabolic and indirectly repressing anabolic enzyme expression. Enzyme expression alone rarely accounts for observed flux changes, and is locally adjusted through passive changes in metabolic concentrations. Abstract : The transcription factor Crp coordinates E. coli 's response to metabolic limitations by directly and indirectly regulating catabolic and anabolic enzyme expression. This regulatory program is adjusted locally through passive changes in metabolite concentrations.