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Classic Spotlight: When Phenotypic Heterogeneity Met Carbon Catabolite Repression Anke Becker LOEWE Center for Synthetic Microbiology, Philipps-Universität Marburg, Marburg, Germany

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henotypic heterogeneity in populations of genetically identical microbial cells has recently developed into a major field of research in microbiology. Observations of cellular individuality in clonal bacterial populations date back to the 1950s, when the “glucose effect” on production of ␤-galactosidase was studied in Escherichia coli. This inhibitory effect of glucose and other carbon sources on induced production of ␤-galactosidase is now known as carbon catabolite repression (CCR). Building on previous observations that, under certain conditions, a bacterial cell may exist in one of two steady states with respect to the synthesis of a certain enzyme system, Cohn and Horibata published three seminal papers in one issue of the Journal of Bacteriology in 1959 (1–3). In these papers, they investigated development of heterogeneity within a clone, maintenance of alternative steady states (production and nonproduction of ␤-galactosidase), and the mechanism of inhibition by glucose. Cohn and Horibata suggested a model explaining maintenance in alternative steady states that shift from one stable state to the other in response to transitory variations in the environment (1, 2). They recognized the importance of the lactose permease for these system properties. Induction of permease synthesis by the substrate and requirement of the permease for substrate uptake are properties of a “self-induced” system. They concluded that any system endowed with such positive feedback properties would tend to show a maintenance effect, a finding that still guides studies of bimodal regulatory systems. Cohn and Horibata were intrigued by previous observations that a large number of structurally unrelated substances could each inhibit the induced synthesis of an equally large number of apparently unrelated enzymes. It was postulated that, for a given induced enzyme, the various inhibitors must be metabolized to a common identical repressor. Cohn and Horibata (3) hypothe-

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sized that glucose itself was metabolized to a repressor, which later was found to be incorrect. It took many more years before the role of enzyme IIA (EIIA) of the phosphotransferase system (PTS) in CCR was uncovered. The simultaneous transport and phosphorylation of glucose increase the level of unphosphorylated EIIA. This unphosphorylated EIIA inhibits adenylate cyclase, leading to low cyclic AMP (cAMP) levels. In turn, cAMP is required for the catabolite activator protein (CAP) to activate transcription of the lac operon. However, only recently have researchers determined that inhibition of the lactose permease by unphosphorylated EIIA is the major CCR mechanism in Enterobacteriaceae, again affirming the well-founded model of Cohn and Horibata, who recognized the importance of the permease for the system. REFERENCES 1. Cohn M, Horibata K. 1959. Inhibition by glucose of the induced synthesis of the ␤-galactoside-enzyme system of Escherichia coli. Analysis of maintenance. J Bacteriol 78:601– 612. 2. Cohn M, Horibata K. 1959. Analysis of the differentiation and of the heterogeneity within a population of Escherichia coli undergoing induced ␤-galactosidase synthesis. J Bacteriol 78:613– 623. 3. Cohn M, Horibata K. 1959. Physiology of the inhibition by glucose of the induced synthesis of the ␤-galactosidase-enzyme system of Escherichia coli. J Bacteriol 78:624 – 635.

Citation Becker A. 2016. Classic spotlight: when phenotypic heterogeneity met carbon catabolite repression. J Bacteriol 198:878. doi:10.1128/JB.00008-16. Address correspondence to [email protected]. Copyright © 2016, American Society for Microbiology. All Rights Reserved. The views expressed in this Editorial do not necessarily reflect the views of the journal or of ASM.

Journal of Bacteriology

March 2016 Volume 198 Number 6

Classic Spotlight: When Phenotypic Heterogeneity Met Carbon Catabolite Repression.

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