Ascites tumor cells are found in the hypoxic environment of the peritoneal
fluid and are largely dependent on glycolysis for energy production. The tissue
capacity of hexokinase is quite low in these cells, and addition of hexokinase
increases the glycolytic rate (J. Biol. Chem. 256, 8699, 1981). However, others
(J. Biol. Chem. 258, 3702, 1983) suggested that glycolysis in these cells was
limited by the ability of Na,K-ATPase to regenerate the Pi consumed at
glyceraldehyde phosphate dehydrogenase. My application of metabolic control
theory (MCT) to a detailed model of ascites cell glycoclysis indicated that
nearly all the control is distributed among the four kinases of the pathway,
suggesting that glycolysis is coherently regulated by the phosphate potential,
just as we were taught in elementary biochemistry class. I also modeled aerobic
metabolism in the perfused rat heart and analyzed the model with MCT. This
exercise indicated that glycolytic control was distributed among those enzymes
(including the mitochondrial respiratory enzymes) which produce or consume ATP.
This reinforces the concept that glycolysis is coherently regulated by the
phosphate potential, which, in turn, is controlled by the enzymes involved in
adenine nucleotide metabolism. Among the cytosolic enzymes, phosphofructo-1-
kinase, pyruvate kinase, and creatine kinase were the major controllers. It
seems to me that searching for a single rate-limiting step in a metabolic
pathway is a futile effort when the constituent enzymes share regulatory
cofactors.
--
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
