The tricarboxylic acid cycle in Dictyostelium discoideum. II. Evaluation of model consistency and robustness.

When kinetic models of complex biochemical systems are reconstructed from knowledge of the component reactions that have been characterized in vitro, or when values must be assumed for some of the parameters, errors are invariably encountered, and, as a consequence, the resulting model is frequently internally inconsistent. The simplest and most basic manifestations of such logical inconsistency are the failure of the model to exhibit a steady state or to yield a steady state that is in agreement with the actual steady state of the integrated system, or to yield a steady state that is dynamically stable. Models that are consistent may nonetheless be lacking in robustness, which is manifested as a pathological sensitivity to small changes in the values of their parameters. In this paper, we examine the current model of the tricarboxylic acid cycle in Dictyostelium discoideum (see Shiraishi, F., and Savageau, M. A. (1992) J. Biol. Chem. 267, 22912-22918) with regard to these basic indicators of model quality. This may be viewed as a preliminary analysis; the object is to determine whether or not the model is reasonable and worthy of a more refined analysis and, if not, to diagnose the areas in need of modification before further analysis is undertaken. The results demonstrate that the current model of the tricarboxylic acid cycle is self-consistent and possesses a steady state that is in agreement with experimental evidence. However, the results also suggest that this model is not very robust. The high sensitivities of parameters influencing pyruvate metabolism indicate that the experimental characterization of these reactions might be fruitfully re-examined. These high sensitivities lead us to predict that this model of the tricarboxylic acid cycle should be accurate only over a very narrow range in variation of the independent variables. This is verified by the results presented in the following paper (Shiraishi, F., and Savageau, M. A. (1992) J. Biol. Chem. 267, 22926-22933).