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1 Metabolic Research Laboratory and Section of Endocrinology, Metabolism and Nutrition, Minneapolis Veterans Affairs Medical Center, and 2 Departments of Medicine and 3 Food Science and Nutrition, University of Minnesota, Minneapolis, Minnesota 55417; and 4 Pfizer Global Research and Development, Groton Laboratories, Groton, Connecticut 06340
Hepatic glucose production is increased in people with type 2 diabetes. Glucose released from storage in liver glycogen by phosphorylase accounts for ~50% of the glucose produced after an overnight fast. Therefore, understanding how glycogenolysis in the liver is regulated is of great importance. Toward this goal, we have determined the kinetic characteristics of recombinant human liver glycogen phosphorylase a (HLGPa) (active form) and compared them with those of the purified rat enzyme (RLGPa). The Michaelis-Menten constant (Km) of HLGPa for Pi, 5 mM, was about fivefold greater than the Km of RLGPa. Two Pi (substrate) concentrations were used (1 and 5 mM) to cover the physiological range for Pi. Other effectors were added at estimated intracellular concentrations. When added individually, AMP stimulated, whereas ADP, ATP and glucose inhibited, activity. These results were similar to those of the RLGPa. However, glucose inhibition was about twofold more potent with the human enzyme. UDP-glucose, glucose 6-phosphate, and fructose 1-phosphate were only minor inhibitors of both enzymes. We reported previously that when all known effectors were present in combination at physiological concentrations, the net effect was no change in RLGPa activity. However, the same combination reduced HLGPa activity, and the inhibition was glucose dependent. We conclude that a combination of the known effectors of phosphorylase a activity, when present at estimated intracellular concentrations, is inhibitory. Of these effectors, only glucose changes greatly in vivo. Thus it may be the major regulator of HLGPa activity.
glucose; glycogen metabolism; enzyme regulation; adenosine 5'-monophosphate; adenosine 5'-diphosphate; adenosine 5'-triphosphate; glucose 1-phosphate; fructose 1-phosphate; uridine 5'-diphosphate-glucose
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