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The role of glucose 6‐phosphate in mediating the effects of glucokinase overexpression on hepatic glucose metabolism
Author(s) -
Härndahl Linda,
Schmoll Dieter,
Herling Andreas W.,
Agius Loranne
Publication year - 2006
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/j.1742-4658.2005.05067.x
Subject(s) - glucokinase , glycogen synthase , glycogen , glycolysis , glycogen branching enzyme , medicine , glycogen phosphorylase , endocrinology , carbohydrate metabolism , glycogenesis , biochemistry , chemistry , metabolism , glucose 6 phosphate , biology , enzyme
Pharmacological activation or overexpression of glucokinase in hepatocytes stimulates glucose phosphorylation, glycolysis and glycogen synthesis. We used an inhibitor of glucose 6‐phosphate (Glc6 P ) hydrolysis, namely the chlorogenic derivative, 1‐[2‐(4‐chloro‐phenyl)‐cyclopropylmethoxy]‐3, 4‐dihydroxy‐5‐(3‐imidazo[4,5‐b]pyridin‐1‐yl‐3‐phenyl‐acryloyloxy)‐cyclohexanecarboxylic acid (also known as S4048), to determine the contribution of Glc6 P concentration, as distinct from glucokinase protein or activity, to the control of glycolysis and glycogen synthesis by glucokinase overexpression. The validity of S4048 for testing the role of Glc6 P was supported by its lack of effect on glucokinase binding and its nuclear/cytoplasmic distribution. The stimulation of glycolysis by glucokinase overexpression correlated strongly with glucose phosphorylation, whereas glycogen synthesis correlated strongly with Glc6 P concentration. Metabolic control analysis was used to determine the sensitivity of glycogenic flux to glucokinase or Glc6 P at varying glucose concentrations (5–20 m m ). The concentration control coefficient of glucokinase on Glc6 P (1.4–1.7) was relatively independent of glucose concentration, whereas the flux control coefficients of Glc6 P (2.4–1.0) and glucokinase (3.7–1.8) on glycogen synthesis decreased with glucose concentration. The high sensitivity of glycogenic flux to Glc6 P at low glucose concentration is consistent with covalent modification by Glc6 P of both phosphorylase and glycogen synthase. The high control strength of glucokinase on glycogenic flux is explained by its concentration control coefficient on Glc6 P and the high control strength of Glc6 P on glycogen synthesis. It is suggested that the regulatory strength of pharmacological glucokinase activators on glycogen metabolism can be predicted from their effect on the Glc6 P content.