An amplified sensitivity arising from covalent modification in biological systems.

Abstract

The transient and steady-state behavior of a reversible covalent modification system is examined. When the modifying enzymes operate outside the region of first-order kinetics, small percentage changes in the concentration ofthe effector controlling either ofthe modifying enzymes can give much larger percentage changes in the amount of modified protein. This amplification of the response to a stimulus can provide additional sensitivity in biological control, equivalent to that of allosteric proteins with high Hill coefficients.Biological systems must respond to internal and external variations such as the depletion of nutrients, the variations in hormone levels, and the reception of sensory signals. The stimuli are processed to change the activities of enzymes controlling pathways in the biological system. Two basic phenomena play a large role in this processing: allosteric changes in protein conformation and covalent modification of proteins.Since the findings of Cori and Green (1) and Krebs and Fischer (2) that glycogen phosphorylase exists in two forms, phosphorylated and dephosphorylated, the number ofproteins that have been found to be controlled by covalent modification has increased steadily. Covalent modification has been identified with control in carbohydrate metabolism, fat metabolism, sensory systems, muscular contraction, protein synthesis, nitrogen metabolism, and malignant transformation (3-10).In phenomena such as sensing, and in the regulation of metabolism, it is important that the "turning on" of one pathway and the "turning off" of another be sensitive to relatively small changes in effector concentration. One known mechanism for increasing the sensitivity of a system is through cooperative interactions. Another is the effect of a ligand that enters at more than one step in a pathway-e.g., to activate one enzyme and inhibit another, as happens in the glycogen cascade (4

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