Abstract
Abstract At neutral pH, concentrations of creatine phosphate comparable to those found in skeletal muscle and heart are highly inhibitory toward rabbit skeletal muscle pyruvate kinase. Creatine phosphate appears to be competitive with phosphoenolpyruvate with a Ki of 2.0 mm. That it is not a simple competition, however, is indicated by the following evidence. The inhibition is increased in the presence of high concentrations of ADP. ATP, a known inhibitor of pyruvate kinase, acts synergistically with creatine phosphate; that is, in the presence of both ATP and creatine phosphate the inhibition is much greater than the sum of the actions of the inhibitors separately. No synergism is seen between ATP and the inhibitory substrate analogue, 2-phosphoglyceric acid. The characteristics of the creatine phosphate effect are quite distinct from the inhibition noted previously with phenylalanine. Phenylalanine inhibition is maximal above pH 8.0 whereas creatine phosphate is more potent at neutral pH. Alanine, which reverses phenylalanine inhibition, has no effect on creatine phosphate inhibition. Phenylalanine does not inhibit the Mn2+-activated enzyme whereas creatine phosphate inhibition is more potent in the presence of manganous ion. Rabbit erythrocyte pyruvate kinase is only slightly inhibited by creatine phosphate. In the presence of the activator, fructose 1,6-diphosphate, the inhibition is much more pronounced. The results are discussed in relation to the regulation of muscle glycolysis and it is suggested that falling creatine phosphate levels may be one of the primary factors contributing to the increase in glycolytic flux that accompanies muscle contraction.
Highlights
At neutral pH, concentrations of creatine phosphate comparable to those found in skeletal muscle and heart are highly inhibitory toward rabbit skeletal muscle pyruvate kinase
Creatine Phosphate Inhibition versus Phenylalanine ZnhibitionTable I shows the effect of increasing concentrations of creatine phosphate on the activity of pyruvate kinase
Comparisons were made with phenylalanine inhibition because it was initially thought that the compounds might be interacting at the same site on the enzyme and that the phenylalanine inhibition was merely the result of nonspecificity of the binding site that is normally employed by creatine phosphate
Summary
At neutral pH, concentrations of creatine phosphate comparable to those found in skeletal muscle and heart are highly inhibitory toward rabbit skeletal muscle pyruvate kinase. Analysis of the concentration of glycolytic intermediates in a number of tissues has indicated that the reaction catalyzed by pyruvate kinase is greatly displaced from equilibrium and may be a regulatory control site (l-3). Studies of the regulatory properties of this enzyme have primarily centered on studies of the isozyme found in the liver and in erythrocytes [4,5,6,7] This isozyme, designated PK I [8] or the L isozyme, is activated by fructose 1,6-diphosphate, which converts the sigmoid response to phosphoenolpyruvate into a hyperbolic saturation curve. It has been difficult to view this as an in viva control mechanism, because the inhibition by phenylalanine is minimal at neutral pH and the concentrations required for significant inhibition are very high
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