Design of Large Metabolic Responses. Constraints and Sensitivity Analysis

✍ Scribed by LUIS ACERENZA

• Publisher: Elsevier Science
• Year: 2000
• Tongue: English
• Weight: 267 KB
• Volume: 207
• Category: Article
• ISSN: 0022-5193
• DOI: 10.1006/jtbi.2000.2173

✦ Synopsis

Metabolic control analysis (Kacser & Burns (1973). Symp. Soc. Exp. Biol. 27, 65}104;Heinrich & Rapoport (1974). Eur. J. Biochem. 42, 89}95) has been extensively used to describe the response of metabolic concentrations and #uxes to small (in"nitesimal) changes in enzyme concentrations and e!ectors. Similarly, metabolic control design (Acerenza (1993). J. theor. Biol. 165, 63}85) has been proposed to design small metabolic responses. These approaches have the limitation that they were not devised to deal with large (non-in"nitesimal) responses.

Here we develop a strategy to design large changes in the metabolic variables. The only assumption made is that, for all the parameter values under consideration, the system has a unique stable steady state. The procedure renders the kinetic parameters of the rate equations that when embedded in the metabolic network produce the pattern of large changes in the steady-state variables that we aim to design. Structural and kinetic constraints impose restrictions on the type of responses that could be designed. We show that these conditions can be transformed into the language of mean-sensitivity coe$cients and, as a consequence, a sensitivity analysis of large metabolic responses can be performed after the system has been designed. The mean-sensitivity coe$cients ful"l conservation and summation relationships that in the limit reduce to the well-known theorems for in"nitesimal changes. Finally, it is shown that the same procedure that was used to design metabolic responses and analyse their sensitivity properties can also be used to determine the values of kinetic parameters of the rate laws operating &&in situ''.