Harpers

METABOLISM OF GLYCOGEN / 151Epinephrine(liver, muscle)Glucagon(liver)PHOSPHODIESTERASEcAMP5′-AMPInhibitor-1Inhibitor-1phosphateGLYCOGENSYNTHASE bPHOSPHORYLASEKINASE bPROTEINPHOSPHATASE-1cAMP-DEPENDENTPROTEIN KINASEPROTEINPHOSPHATASE-1GLYCOGENSYNTHASE aPHOSPHORYLASEKINASE aGlycogenUDPGIcGlycogencyclePHOSPHORYLASEaPHOSPHORYLASEbGlucose 1-phosphatePROTEINPHOSPHATASE-1Glucose (liver)GlucoseLactate (muscle)Figure 18–8. Coordinated control of glycogenolysis and glycogenesis by cAMP-dependent protein kinase.The reactions that lead to glycogenolysis as a result of an increase in cAMP concentrations are shownwith bold arrows, and those that are inhibited by activation of protein phosphatase-1 are shown as brokenarrows. The reverse occurs when cAMP concentrations decrease as a result of phosphodiesterase activity,leading to glycogenesis.the dephosphorylation of phosphorylase a, phosphorylasekinase a, and glycogen synthase b is catalyzed bya single enzyme of wide specificity—protein phosphatase-1.In turn, protein phosphatase-1 is inhibitedby cAMP-dependent protein kinase via inhibitor-1.Thus, glycogenolysis can be terminated and glycogenesiscan be stimulated synchronously, or vice versa, becauseboth processes are keyed to the activity of cAMP-dependentprotein kinase. Both phosphorylase kinase andglycogen synthase may be reversibly phosphorylated inmore than one site by separate kinases and phosphatases.These secondary phosphorylations modify the sensitivityof the primary sites to phosphorylation and dephosphorylation(multisite phosphorylation). What ismore, they allow insulin, via glucose 6-phosphate elevation,to have effects that act reciprocally to those ofcAMP (Figures 18–6 and 18–7).CLINICAL ASPECTSGlycogen Storage Diseases Are Inherited“Glycogen storage disease” is a generic term to describea group of inherited disorders characterized by depositionof an abnormal type or quantity of glycogen in thetissues. The principal glycogenoses are summarized inTable 18–2. Deficiencies of adenylyl kinase andcAMP-dependent protein kinase have also been re-