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J. Biol. Chem., Vol. 276, Issue 26, 23858-23866, June 29, 2001
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From the We used metabolic control analysis to determine
the flux control coefficient of phosphorylase on glycogen synthesis in
hepatocytes by titration with a specific phosphorylase inhibitor
(CP-91149) or by expression of muscle phosphorylase using recombinant
adenovirus. The muscle isoform was used because it is catalytically
active in the b-state. CP-91149 inactivated phosphorylase
with sequential activation of glycogen synthase. It increased glycogen
synthesis by 7-fold at 5 mM glucose and by 2-fold at 20 mM glucose with a decrease in the concentration of
glucose causing half-maximal rate (S0.5) from 26 to 19 mM. Muscle phosphorylase was expressed in hepatocytes
mainly in the b-state. Low levels of phosphorylase expression inhibited glycogen synthesis by 50%, with little further inhibition at higher enzyme expression, and caused inactivation of
glycogen synthase that was reversed by CP-91149. At endogenous activity, phosphorylase has a very high (greater than unity) negative control coefficient on glycogen synthesis, regardless of whether it is determined by enzyme inactivation or overexpression. This high
control is attenuated by glucokinase overexpression, indicating dependence on other enzymes with high control. The high control coefficient of phosphorylase on glycogen synthesis affirms that phosphorylase is a strong candidate target for controlling
hyperglycemia in type 2 diabetes in both the absorptive and
postabsorptive states.
Hepatic Glycogen Synthesis Is Highly Sensitive to Phosphorylase
Activity
EVIDENCE FROM METABOLIC CONTROL ANALYSIS*
,,¶
Department of Diabetes, University of
Newcastle upon Tyne, The Medical School, Newcastle upon Tyne NE2 4HH,
United Kingdom, and § Departament de Bioquímica i
Biologia Molecular, Universitat de Barcelona, Martí i
Franquès, 1, 08028 Barcelona, Spain
*
This work was supported by the Medical Research Council and
by the Royal Society through an award under the European Science Exchange Programme.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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