OCISB Seminar "Sensitivity and Robustness in Bifunctional Enzyme Systems: Reconciling Ultrasensitivity with Bifunctionality"

Biological systems have to operate reliably under changing environmental conditions which makes it necessary that the underlying regulatory networks are robust with respect to some perturbations while remaining sensitive to others. Regulation by covalent modification is a common mechanism to transmit signals in biological systems. Intriguingly, there exist two architectures for this purpose: Either modification and demodification are catalyzed by distinct converter enzymes or both reactions are carried out by a single bifunctional enzyme. Theoretical studies predict that covalent modification cycles with two converter enzymes can exhibit zero-order ultrasensitivity (ZOUS) whereas a bifunctional design of the converter enzyme has been associated with a particular form of robustness called absolute concentration robustness (ACR). However, the first experimental evidence for an enhanced sensitivity due to the zero-order effect actually came from studies with a bifunctional enzyme system raising the question about the underlying mechanism. Here, I show that bifunctional enzymes with two catalytic sites cannot only exhibit ACR, but also ZOUS similarly as CMCs with distinct converter enzymes. Comparison of the theoretical results with experimental observations of ZOUS in the phosphorylation cycle of the isocitrate dehydrogenase and the uridylylation cycle of the PII protein yield remarkable agreement. Together, these results provide a rationale for the experimental observations of ZOUS in bifunctional enzyme systems. They also show how sensitivity and robustness can arise from the same regulatory mechanism. ALL INVITED