On the Validity of the Stochastic Quasi-Steady-State Approximation in Open Enzyme Catalyzed Reactions: Timescale Separation or Singular Perturbation?

The quasi-steady-state approximation is widely used to develop simplified deterministic or stochastic models of enzyme catalyzed reactions. In deterministic models, the quasi-steady-state approximation can be mathematically justified from singular perturbation theory. For several closed enzymatic reactions, the homologous extension of the quasi-steady-state approximation to the stochastic regime, known as the stochastic quasi-steady-state approximation, has been shown to be accurate under the analogous conditions that permit the quasi-steady-state reduction in the deterministic counterpart. However, it was recently demonstrated that the extension of the stochastic quasi-steady-state approximation to an open Michaelis-Menten reaction mechanism is only valid under a condition that is far more restrictive than the qualifier that ensures the validity of its corresponding deterministic quasi-steady-state approximation. In this paper, we suggest a possible explanation for this discrepancy from the lens of geometric singular perturbation theory. In so doing, we illustrate a misconception in the application of the quasi-steady-state approximation: timescale separation does not imply singular perturbation.