首页 | 本学科首页   官方微博 | 高级检索  
   检索      


Endogenous effectors of human liver glycogen phosphorylase modulate effects of indole-site inhibitors
Authors:Ercan-Fang Nacide  Taylor Miriam R  Treadway Judith L  Levy Carolyn B  Genereux Paul E  Gibbs E Michael  Rath Virginia L  Kwon Younggil  Gannon Mary C  Nuttall Frank Q
Institution:Metabolic Research Laboratory, Section of Endocrinology, Metabolism, and Nutrition, Minneapolis Veterans Affairs Medical Center, Minneapolis, MN 55417, USA. ercan001@umn.edu
Abstract: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 microM), 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.
Keywords:
本文献已被 PubMed 等数据库收录!
设为首页 | 免责声明 | 关于勤云 | 加入收藏

Copyright©北京勤云科技发展有限公司  京ICP备09084417号