This paper explores the sensitivity of covalent modification systems in biological processes. The authors show that when modifying enzymes operate outside the first-order kinetics region, small changes in effector concentration can lead to large changes in the amount of modified protein. This amplification of the response to a stimulus can provide additional sensitivity in biological control, similar to that of allosteric proteins with high Hill coefficients. The study examines a covalent modification system where a protein can exist in unmodified (W) or modified (W*) forms. The interconversion of these forms is catalyzed by two enzymes, E1 and E2. The kinetic equations governing the system show that the fraction of modified protein (W*) depends on the ratio of the modification rates (V1/V2) and the Michaelis constants (K1 and K2). The results reveal that when one or more of the converter enzymes operate in the "zero-order" region (saturation with respect to protein substrate), the system exhibits "zero-order ultrasensitivity," which is more sensitive to changes than the Michaelis-Menten response. The authors also discuss the effect of nonproductive binding and appreciable concentrations of enzyme-substrate complexes on the system's sensitivity. They show that the presence of these complexes can reduce the steepness of the transition between unmodified and modified protein. However, when the modifying enzymes are saturated with substrates, the sensitivity can be significantly increased. The study further examines the behavior of a bicyclic cascade, where the modified protein from the first cycle catalyzes the modification of a second target protein. The results show that the second cycle can amplify the sensitivity of the first cycle, leading to a steeper response curve. The authors also discuss the time required for the system to reach a new steady state after a stimulus. They show that the time can be relatively short, on the order of seconds, depending on the kinetic parameters. However, if the change in the ratio of modification rates is slow, the response may be delayed. The paper concludes that covalent modification systems can provide enhanced sensitivity through three mechanisms: conventional cooperative ultrasensitivity, multistep ultrasensitivity, and zero-order ultrasensitivity. These mechanisms allow biological systems to respond more sensitively to small changes in environmental stimuli, which is essential for tight control of physiological processes. The findings suggest that covalent modification is a valuable mechanism for achieving high sensitivity in biological systems.This paper explores the sensitivity of covalent modification systems in biological processes. The authors show that when modifying enzymes operate outside the first-order kinetics region, small changes in effector concentration can lead to large changes in the amount of modified protein. This amplification of the response to a stimulus can provide additional sensitivity in biological control, similar to that of allosteric proteins with high Hill coefficients. The study examines a covalent modification system where a protein can exist in unmodified (W) or modified (W*) forms. The interconversion of these forms is catalyzed by two enzymes, E1 and E2. The kinetic equations governing the system show that the fraction of modified protein (W*) depends on the ratio of the modification rates (V1/V2) and the Michaelis constants (K1 and K2). The results reveal that when one or more of the converter enzymes operate in the "zero-order" region (saturation with respect to protein substrate), the system exhibits "zero-order ultrasensitivity," which is more sensitive to changes than the Michaelis-Menten response. The authors also discuss the effect of nonproductive binding and appreciable concentrations of enzyme-substrate complexes on the system's sensitivity. They show that the presence of these complexes can reduce the steepness of the transition between unmodified and modified protein. However, when the modifying enzymes are saturated with substrates, the sensitivity can be significantly increased. The study further examines the behavior of a bicyclic cascade, where the modified protein from the first cycle catalyzes the modification of a second target protein. The results show that the second cycle can amplify the sensitivity of the first cycle, leading to a steeper response curve. The authors also discuss the time required for the system to reach a new steady state after a stimulus. They show that the time can be relatively short, on the order of seconds, depending on the kinetic parameters. However, if the change in the ratio of modification rates is slow, the response may be delayed. The paper concludes that covalent modification systems can provide enhanced sensitivity through three mechanisms: conventional cooperative ultrasensitivity, multistep ultrasensitivity, and zero-order ultrasensitivity. These mechanisms allow biological systems to respond more sensitively to small changes in environmental stimuli, which is essential for tight control of physiological processes. The findings suggest that covalent modification is a valuable mechanism for achieving high sensitivity in biological systems.