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CASE FILES: BIOCHEMISTRY
Insulin
f
t
-
PP1
r
GlycogenQ'/ /
V ©
Cl
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Glucose
G lucose
G6P
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Figure 22-2a. Insulin stimulation of the flux of glucose through the glycolytic
pathway. Insulin activates protein phosphatase 1, which in turn activates glycogen
synthase, phosphofructokinase, and pyruvate kinase. Abbreviations: fructose
1,6-bisphosphate (F1,6BisP); fructose 6-phosphate (F6P); glucose 1-phosphate
(G1P); glucose 6-phosphate (G6P); glycogen phosphorylase (GP); glycogen
synthase (GS); phosphoenolpyruvate (PEP); phosphofructokinase (PFK); pyru-
vate kinase (PK); protein phosphatase 1 (PP1)
will stimulate net glycogen synthesis (glycogenesis) by liver and muscle, in
response to insulin. One way in which insulin promotes PP1-mediated effects
on glycogen metabolism is through the targeting of PP1 to the glycogen parti-
cle, a subcellular domain comprised of glycogen itself, as well as the enzymes
required for glycogen synthesis and degradation. The glycogen binding subunit
is a docking protein allowing PP1 association with the glycogen particle.
Insulin induces tyrosine phosphorylation of this glycogen binding subunit,
thereby promoting PP1 binding and therefore increased glycogenesis.
The glycogen capacity of a cell is of finite size. Once this capacity is
reached, excess glucose must undergo alternative metabolic fates. Insulin pro-
motes flux of glucose through the glycolytic pathway (glucose ^ 2 pyruvate),
again in part through PP1 activation (see Fig. 22-2a). As glycogenolysis is the
reciprocal pathway to glycogenesis, gluconeogenesis (the synthesis of glucose)
is the reciprocal pathway to glycolysis. Gluconeogenesis occurs primarily in
the liver and to a lesser extent in the kidney. PP1 increases glycolytic flux in
the liver through activation of phosphofructokinase (PFK; indirect effect
through dephosphorylation of a bifunctional enzyme, resulting in increased intra-
cellular levels of fructose 2,6-bisphosphate, an allosteric activator of PFK) and
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