Chapter 6 Cyclic cascades in cellular regulation

Abstract

Summary The cyclic cascade model, derived mainly from detailed studies of E. coli glutamine synthetase, is applicable to all covalent interconvertible enzyme systems. The regulatory mechanism makes use of both covalent modification and allosteric interactions. Analysis of this model reveals its regulatory advantages, which include signal amplification, rate amplification, sensivity, and flexibility. Most of the properties predicted by theoretical analysis have been verified experimentally by in vitro studies of the phosphorylation/dephosphorylation cycle and the glutamine synthetase cascade, and by studies on permeabilized cells. By means of allosteric interactions with one or more enzymes, cyclic cascades can continuously monitor fluctuations in the concentrations of a multitude of metabolites and adjust the specific activities of the target enzymes in response to biological requirement. Therefore, they serve as biological integrators with the capacity to provide a safeguard mechanism for biological systems. With the enormous capacity for signal and rate amplification, cyclic cascades provide an ideal mechanism for biological signal transduction. Although a cyclic cascade modulates the specific activity of the interconvertible enzyme smoothly and continuously over a wide range of conditions, it can provide transient responses to biological stimuli, and in extreme physiological situations serve as an on-off switch for the activity of the target enzyme. The energy for maintaining such an efficient regulatory mechanism is the consumption of ATP and other energy-rich donor molecules. In view of the unique properties of cyclic cascades, it should not be surprising that they are widely used for transmitting biological signals and for regulating both the activities and biosynthesis of key enzymes.