Inhibition of Muscle Pyruvate Kinase by Creatine Phosphate
Robert G. Kemp 1
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1 From the Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 53233
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.
Submitted on February 5, 1973
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