title: Modeling networks of coupled enzymatic reactions using the total quasi-steady state approximation.
abstract: In metabolic networks, metabolites are usually present in great excess over the enzymes that catalyze their interconversion, and describing the rates of these reactions by using the Michaelis-Menten rate law is perfectly valid. This rate law assumes that the concentration of enzyme-substrate complex (C) is much less than the free substrate concentration (S0). However, in protein interaction networks, the enzymes and substrates are all proteins in comparable concentrations, and neglecting C with respect to S0 is not valid. Borghans, DeBoer, and Segel developed an alternative description of enzyme kinetics that is valid when C is comparable to S0. We extend this description, which Borghans et al. call the total quasi-steady state approximation, to networks of coupled enzymatic reactions. First, we analyze an isolated Goldbeter-Koshland switch when enzymes and substrates are present in comparable concentrations. Then, on the basis of a real example of the molecular network governing cell cycle progression, we couple two and three Goldbeter-Koshland switches together to study the effects of feedback in networks of protein kinases and phosphatases. Our analysis shows that the total quasi-steady state approximation provides an excellent kinetic formalism for protein interaction networks, because (1) it unveils the modular structure of the enzymatic reactions, (2) it suggests a simple algorithm to formulate correct kinetic equations, and (3) contrary to classical Michaelis-Menten kinetics, it succeeds in faithfully reproducing the dynamics of the network both qualitatively and quantitatively.
authors: The FIRC Institute for Molecular Oncology, Milan, Italy. andrea.ciliberto@ifom-ieo-campus.it
authors: Andrea
authors: A
authors: Ciliberto
authors: Fabrizio
authors: F
authors: Capuani
authors: John J
authors: JJ
authors: Tyson
mesh_terms: D000465:Algorithms; D003198:Computer Simulation; D006706:Homeostasis / Q000502:physiology*; D007700:Kinetics; D008954:Models, Biological; D009097:Multienzyme Complexes / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D009097:Multienzyme Complexes