Design of large metabolic responses. Constraints and sensitivity analysis

Area of Science:

• Systems Biology
• Metabolic Engineering
• Biochemical Engineering

Background:

• Metabolic control analysis (MCA) and metabolic control design traditionally focus on infinitesimal changes in metabolic systems.
• Existing methods are limited in their ability to design or analyze large, non-infinitesimal responses in metabolic concentrations and fluxes.

Purpose of the Study:

• To develop a novel strategy for designing substantial, non-infinitesimal changes in metabolic variables.
• To enable the engineering of metabolic networks for specific, large-scale alterations in steady-state behavior.

Main Methods:

• A new procedure is developed to determine kinetic parameters for achieving desired large changes in metabolic steady-state variables.
• The approach assumes a unique stable steady state for the system across relevant parameter values.
• Structural and kinetic constraints are analyzed and translated into mean-sensitivity coefficients.

Main Results:

• The developed strategy successfully designs large metabolic responses by specifying kinetic parameters.
• Mean-sensitivity coefficients are used to perform sensitivity analysis on these large responses.
• Conservation and summation relationships for mean-sensitivity coefficients are shown to reduce to known theorems for infinitesimal changes in the limit.

Conclusions:

• The new method provides a framework for designing and analyzing large metabolic responses, expanding upon traditional MCA.
• It allows for the determination of kinetic parameters operating 'in situ' within metabolic networks.
• This approach offers enhanced control and predictability for metabolic engineering applications.