Quasi steady-state approximations in complex intracellular signal transduction networks - a word of caution

Enzyme reactions play a pivotal role in intracellular signal transduction. Many enzymes are known to possess Michaelis–Menten (MM) kinetics and the MM approximation is often used when modeling enzyme reactions. However, it is known that the MM approximation is only valid at low enzyme concentrations, a condition not fulfilled in many in vivo situations. Recently the total quasi steady-state approximation (tQSSA) has been developed for enzymes with MM kinetics. This new approximation is valid not only whenever the MM approximation is, but moreover in a greatly extended parameter range. Starting from a single reaction and arriving at the mitogen activated protein kinase (MAPK) cascade, we give several examples of biologically realistic scenarios where the MM approximation leads to quantitatively as well as qualitatively wrong conclusions, and show that the tQSSA improves the accuracy of the simulations greatly.