Carbon catabolite repression (CCR) is one of the most intensively studied systems in molecular biology; yet many mysteries remain, regarding its physiological function and molecular implementation. We investigated these issues using a quantitative physiological approach. Through extensive characterization of the growth and expression of exemplary metabolic genes using a variety of mutants under many combinations of nutrient limitations, we revealed striking linear relations linking the expressions of catabolic genes and the rate of cell growth in E. coli. They can be understood in terms of two powerful constraints governing cell growth and metabolism: the balance of metabolic fluxes which is well known, and the partitioning of the ribosomal load which is not widely appreciated. The results of our study establish that CCR is not about hierarchical carbon uptake as commonly thought, but about the coordination between catabolism and biosynthesis. Furthermore, we show that this coordination is implemented molecularly by an integral feedback scheme involving metabolic precursors such as alpha ketoacids. Finally, we describe mechanisms implementing carbon hierarchy and show how CCR fits in the scheme, for cultures growing on combinations of carbon sources. Our findings demonstrate the power of the “top-down approach,” both in providing predictive understandings of physiological responses and in elucidating key regulatory mechanisms that evaded extensive molecular studies.

References

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Rabinowitz JD, Silhavy TJ. Systems biology: metabolite turns master regulator. Nature. 2013 Aug 15;500(7462):283-4.