Mathematical Analysis of Activation Thresholds in Enzyme-Catalyzed Positive Feedbacks: Application to the Feedbacks of Blood Coagulation

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 92; no. 19; pp. 8744 - 8748
• Main Authors: Beltrami, Edward, Jesty, Jolyon
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 12.09.1995; National Acad Sciences; National Academy of Sciences
• Subjects: Blood coagulation; Blood Coagulation - physiology; Blood Coagulation Factors - metabolism; Catalysts; Clotting; Coagulation; Computer Simulation; Control loops; Eigenvalues; Enzyme Activation; Enzymes; Feedback; Kinetics; Mathematical constants; Mathematical models; Models, Biological; Positive feedback; Zymogens
• DOI: 10.1073/pnas.92.19.8744
• ISSN: 0027-8424

A hierarchy of enzyme-catalyzed positive feedback loops is examined by mathematical and numerical analysis. Four systems are described, from the simplest, in which an enzyme catalyzes its own formation from an inactive precursor, to the most complex, in which two sequential feedback loops act in a cascade. In the latter we also examine the function of a long-range feedback, in which the final enzyme produced in the second loop activates the initial step in the first loop. When the enzymes generated are subject to inhibition or inactivation, all four systems exhibit threshold properties akin to excitable systems like neuron firing. For those that are amenable to mathematical analysis, expressions are derived that relate the excitation threshold to the kinetics of enzyme generation and inhibition and the initial conditions. For the most complex system, it was expedient to employ numerical simulation to demonstrate threshold behavior, and in this case long-range feedback was seen to have two distinct effects. At sufficiently high catalytic rates, this feedback is capable of exciting an otherwise subthreshold system. At lower catalytic rates, where the long-range feedback does not significantly affect the threshold, it nonetheless has a major effect in potentiating the response above the threshold. In particular, oscillatory behavior observed in simulations of sequential feedback loops is abolished when a long-range feedback is present.