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This Article Full Text Full Text (PDF) All Versions of this Article: 289/3/E366    most recent 00264.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by Ercan-Fang, N. Articles by Nuttall, F. Q. Search for Related Content PubMed PubMed Citation Articles by Ercan-Fang, N. Articles by Nuttall, F. Q.

Endogenous effectors of human liver glycogen phosphorylase modulate effects of indole-site inhibitors

¹Metabolic Research Laboratory, Section of Endocrinology, Metabolism, and Nutrition, Minneapolis Veterans Affairs Medical Center and ⁵Departments of Medicine and Food Science and Nutrition, University of Minnesota, Minneapolis, Minnesota; Departments of ²Cardiovascular and Metabolic Diseases, ³Molecular Sciences, and ⁴Pharmacokinetics, Dynamics, and Metabolism, Pfizer Global Research and Development, Groton Laboratories, Groton, Connecticut

Submitted 22 June 2004 ; accepted in final form 28 March 2005

Phosphorylase is regulated by a number of small-molecular-weight effectors that bind to three sites on the enzyme. Recently, a fourth site referred to as the indole-inhibitor site has been identified. Synthetic compounds bind to the site and inhibit activity. However, the effects of these compounds in the presence of other endogenous effectors are unknown. We have determined the effects of four indole derivative glycogen phosphorylase inhibitors (GPI) on recombinant human liver glycogen phosphorylase a activity. The GPIs tested were all potent inhibitors. However, the endogenous inhibitors (glucose, ADP, ATP, fructose 1-phosphate, glucose 6-phosphate, UDP-glucose) and the activator (AMP) markedly reduced the inhibitory effect of GPIs. Consistent with these in vitro findings, the IC₅₀ for the inhibition of glycogenolysis in cells and the liver drug concentration associated with glucose-lowering activity in diabetic ob/ob mice in vivo were also significantly higher than those determined in in vitro enzyme assays. The inhibitory effect of indole-site effectors is modulated by endogenous small-molecular-weight effectors of phosphorylase a activity. However, at higher concentrations (10–30 µM), the GPI effect was dominant and resulted in inhibition of phosphorylase a activity irrespective of the presence or absence of the other modulators of the enzyme.

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