J. Biol. Chem., Vol. 267, Issue 32, 22919-22925, 11, 1992
The tricarboxylic acid cycle in Dictyostelium discoideum. II. Evaluation of model consistency and robustness
F Shiraishi and MA Savageau
Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor 48109-0620.
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).
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