Theoretical study on preference of metabolic fuels in heart muscle cells
Popova, S.V.; Reich, J.G.
Acta Biologica et Medica Germanica 40(3): 217-226
1981
ISSN/ISBN: 0001-5318 PMID: 7304037 Document Number: 174300
A kinetic model is proposed which describes fuel preference in heart muscle cells. Preference of acetate to pyruvate is formulated as the basic model because this is the situation with the simplest stoichiometry and mathematical description. This model is formulated in terms of mass-action kinetics and does not take into account the well-known non-stoichiometric signals. The basic model predicts a drastic reduction of pyruvate uptake by the addition of acetate. This is caused by a cooperative kinetic effect of the decreased levels of CoASH and NAD+. The decrease in CoASH is explained by the requirement of acetate thiokinase for that cofactor, and that in NAD+ by the increased competitive capacity of the citric acid cycle. Regulatory signals of ATP/ADP and NADH/NAD+ on pyruvate dehydrogenase and citrate synthase make these competitive efects somewhat more pronounced, but not essentially different in character. The rise in acetyl-CoA and NADH concentrations and the decreased rate of pyruvate oxidation obtained with the basic model are in good agreement with published experiments. Comparison of the apparent Michaelis constants with cellular metabolite concentrations shows that the use of approximated mass-action rate laws is justified. Competitive inhibition of pyruvate dehydrogenase by acetyl-CoA, which is often regarded as the decisive regulatory factor in the switching-over from carbohydrate to fatty acid oxidation, is shown to be only a tuning signal that brings the apparent Michaelis constant of pyruvate dehydrogenase into the range of the cellular CoASH concentration.