On Aug 31, 4:54pm, Petr Kuzmic wrote:
>> Is is not true that the dynamics of enzyme systems can be solved in full
> generality, by numerical integration of an appropriate system of
> nonlinear first-order ODE's? In this general numerical approach, we do
> not have to make any assumptions about constancy or nonconstancy of
> surrounging concentrations.
>> I have in mind the work started by David Garfinkel [Garf6654] and
> brought to a certain milestone in the form of Hayashi & Sakamoto's book
> [Haya85]. How does the numerical approach fit into MCA? Haven't we
> (effectively) "moved from the ideal case ... to real ones" ever since
> Alan Hindmarsh [Hind8355,Byrn8701] designed his collection of ODE
> solvers?
>> Please help me understand what the problem is in "moving from the ideal"
> case: I think it has been done.
>>-- End of excerpt from Petr Kuzmic
David Garfinkel and I worked closely for over 10 years in developing highly
detailed models of intermediary metabolism in heart and liver (see the list of
our publications in my Web pages at the URL below). These models typically
included representations of about 60 to 70 enzymes in pathways linked by shared
substrates and cofactors (e.g. glycolysis, citric acid cycle, malate-aspartate
shuttle, fatty acid activation and oxidation, and the various membrane
transport proteins required to maintain compartmentation). I have applied MCA
to many of these models in toto--not treating each pathway in isolation--and
compared its predictions for control of glycolysis to those of a model of
isolated glycolysis in ascites tumor cells (which grow under hypoxic conditions
and are largely dependent on anaerobic metabolism to supply their energy
needs). The results were strikingly similar; those reactions which regulated
the ATP/ADP ratio were by far the most important regulators of flux regardless
of whether the pathway was operating under aerobic or anaerobic conditions.
Under aerobic conditions, the mitochondrial enzymes which contribute to ATP
production and delivery to the cytosol are as important in regulating
glycolytic flux as are the glycolytic enzymes. In those cases where I
simplified the model by omitting certain enzymatic reactons, the predicted
control by other reactions was exaggerated. Furthermore, although the theorems
of MCA being discussed in this thread have a strict requirement for a steady
state, my analysis, which is based on linear perturbation analysis and is
identical to the formulations of Kacser & Burns and Heinrich & Rapoport under
steady-state conditions, can be used (for a very rough approximation) under any
conditions and shows that the same enzymes can be the primary regulators in
steady and nonsteady states.
--
Michael C. Kohn
Laboratory of Computational Biology and Risk Analysis
National Institute of Environmental Health Sciences
P.O. Box 12233, Mail Drop A3-06
Research Triangle Park, NC 27709-2233
Telephone:
919-541-4929 (voice)
919-541-1479 (fax)
e-mail:
kohn at valiant.niehs.nih.gov
WWW home page:
http://valiant.niehs.nih.gov
