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Articles in PresS, published online ahead of print March 5, 2002
Am J Physiol Endocrinol Metab, 10.1152/ajpendo.00425.2001
Submitted on September 24, 2001
Accepted on March 3, 2002
1 Metabolic-Endocrine, VA Medical Center, Minneapolis, MN, USA; Medicine, University of Minnesota, Minneapolis, MN, USA
2 Metabolic-Endocrine, VA Medical Center, Minneapolis, MN, USA; Medicine, University of Minnesota, Minneapolis, MN, USA; Food Science and Nutrition, University of Minnesota, Minneapolis, MN, USA
3 Global Research and Developement, Pfizer Inc., Groton, CT, USA
4 Metabolic-Endocrine, VA Medical Center, Minneapolis, MN, USA
* To whom correspondence should be addressed. E-mail: ercan001{at}tc.umn.edu.
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. Towards this goal we have determined the kinetic characteristics of recombinant human liver glycogen phosphorylase a (HLGPa) (active form) and compared them to those of the purified rat enzyme (RLGPa). Activity in the direction of glycogenolysis, under initial rate conditions was measured. The Km of HLGPa for Pi (inorganic phosphate), 5mM, was ~5-fold greater than the Km of RLGPa. Two Pi (substrate) concentrations were used (1 and 5mM) 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 ~2-fold more potent with the human enzyme. It reduced the activity to 31% (8mM glucose) and 10% (20mM glucose) of the control at 1mM Pi, and to 56% and 23%, respectively, at 5mM Pi. UDP-glucose, glucose-6-P, fructose-1-P 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 to 34% (8mM glucose) and 17% (20mM glucose) of the control at 1mM Pi concentration. At 5mM Pi it was reduced to 47% and 29%, respectively. These results are similar to those observed with glucose alone. Conclusion: 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.
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