The Quasi-Steady-State Approximations revisited: Timescales, small parameters, singularities, and normal forms in enzyme kinetic

TL;DR

This paper revisits quasi-steady-state approximations in enzyme kinetics, providing refined error bounds, expanding their validity conditions, and analyzing the singularities and bifurcations in their critical manifolds.

Contribution

It introduces improved bounds on approximation errors, broadens the validity domain of the reverse quasi-steady-state approximation, and analyzes the associated singularities and bifurcations.

Findings

Reverse quasi-steady-state approximation valid at equal enzyme and substrate concentrations.

New small parameter determines the validity of the reverse approximation.

Identified a singular point with a transcritical bifurcation in the critical manifold.

Abstract

In this work, we revisit the scaling analysis and commonly accepted conditions for the validity of the standard, reverse and total quasi-steady-state approximations through the lens of dimensional Tikhonov-Fenichel parameters and their respective critical manifolds. By combining Tikhonov-Fenichel parameters with scaling analysis and energy methods, we derive improved upper bounds on the approximation error for the standard, reverse and total quasi-steady-state approximations. Furthermore, previous analyses suggest that the reverse quasi-steady-state approximation is only valid when initial enzyme concentrations greatly exceed initial substrate concentrations. However, our results indicate that this approximation can be valid when initial enzyme and substrate concentrations are of equal magnitude. Using energy methods, we find that the condition for the validity of the reverse quasi-steady-state approximation is far less restrictive than was previously assumed, and we derive a new "small" parameter that determines the validity of this approximation. In doing so, we extend the established domain of validity for the reverse quasi-steady-state approximation. Consequently, this opens up the possibility of utilizing the reverse quasi-steady-state approximation to model enzyme catalyzed reactions and estimate kinetic parameters in enzymatic assays at much lower enzyme to substrate ratios than was previously thought. Moreover, we show for the first time that the critical manifold of the reverse quasi-steady-state approximation contains a singular point where normal hyperbolicity is lost. Associated with this singularity is a transcritical bifurcation, and the corresponding normal form of this bifurcation is recovered through scaling analysis.