134 11.

Glycogen Metabolism

b. Calcium activation of liver phosphorylase kinase: During

“fight or flight” situations, epinephrine is released from the
Ca 2+
Endoplasmic Ca 2+
adrenal medulla and signals the need for blood glucose. This
reticulum Ca 2+ glucose initially comes from hepatic glycogenolysis. Binding of
epinephrine to hepatocyte α-adrenergic G protein-coupled
receptors activates a phospholipid-dependent cascade (see
Ca 2+ is released from the
endoplasmic reticulum
p. 205) that results in movement of Ca2+ from the ER into the
in response to hormones cytoplasm. A Ca2+-calmodulin complex forms and activates
or neurotransmitters hepatic phosphorylase kinase b. [Note: The released Ca2+ also
binding to cell-surface
receptors.
helps to activate protein kinase C that can phosphorylate (thus
inactivate) glycogen synthase a.]

Ca 2+ 3. Activation of glycogen degradation in muscle by AMP: Muscle

glycogen phosphorylase is active in the presence of the high AMP
Calmodulin
concentrations that occur in the muscle under extreme conditions
of anoxia and ATP depletion. AMP binds to glycogen phosphory-
lase b, causing its activation without phosphorylation (see Figure
Ca 2+ Ca 2+
Calmodulin-
+
dulin- 11.9). [Note: Recall that AMP also activates PFK-1 of glycolysis
Ca2 complex
mplex (see p. 99).]
Ca 2+ Ca 2+

VI. GLYCOGEN STORAGE DISEASES

The transient increase
in the intracellular Ca 2+ These are a group of genetic diseases that result from a defect in an
concentration favors the enzyme required for glycogen synthesis or degradation. They result
formation of the either in formation of glycogen that has an abnormal structure, or in the
calmodulin-Ca 2+complex.
accumulation of excessive amounts of normal glycogen in specific tis-
sues as a result of impaired degradation. A particular enzyme may be
defective in a single tissue, such as liver (resulting in hypoglycemia) or
Inactive enzyme muscle (muscle weakness), or the defect may be more generalized,
affecting liver, muscle, kidney, intestine, and myocardium. The severity
of the glycogen storage diseases (GSDs) ranges from fatal in infancy to
mild disorders that are not life-threatening. Some of the more prevalent
Ca 2+ Ca 2+
GSDs are illustrated in Figure 11.8.
Calmodulin-
Ca2+complex
p
Ca 2+ Ca 2+
VII. CHAPTER SUMMARY
Active enzyme
The main stores of glycogen in the body are found in skeletal muscle ,
where they serve as a fuel reserve for the synthesis of ATP during
muscle contraction, and in the liver, where they are used to maintain
Substrate
trate Product the blood glucose concentration, particularly during the early stages
of a fast. Glycogen is a highly branched polymer of -D-glucose. The
primary glycosidic bond is an (1 4) linkage. After about eight to ten
The calmodulin-Ca 2+complex glucosyl residues, there is a branch containing an (1 6) linkage.
is an essential component of
many Ca 2+-dependent UDP-glucose , the building block of glycogen, is synthesized from
enzymes. glucose 1-phosphate and UTP by UDP-glucose pyrophosphorylase
(Figure 11.13). Glucose from UDP-glucose is transferred to the nonre-
ducing ends of glycogen chains by primer-requir ing glycogen
Figure 11.12 synthase, which makes (1 4) linkages. The primer is made by glyco-
Calmodulin mediates many effects
of intracellular calcium. genin. Branches are formed by amylo- (1 4) (1 6)-transglucosi-
dase, which transfers a chain of six to eight glucosyl residues from the
nonreducing end of the glycogen chain (breaking an (1 4) linkage),
and attaches it with an (1 6) linkage to another residue in the chain.
VII. Chapter Summary 135

PLP-requiring glycogen phosphorylase cleaves the (1 4) bonds between glucosyl residues at the nonreduc-
ing ends of the glycogen chains, producing glucose 1-phosphate . This sequential degradation continues until
four glucosyl units remain on each chain before a branch point. The resulting structure is called a limit dextrin
that is degraded by the bifunctional debranching enzyme. Oligo- (1 4) (1 4)-glucan transferase (common
name, glucosyl 4:4 transferase ) removes the outer three of the four glucosyl residues attached at a branch, and
transfers them to the nonreducing end of another chain where they can be converted to glucose 1-phosphate by
glycogen phosphorylase. Next, the remaining single glucose residue attached in an (1 4) linkage is removed
hydrolytically by the amylo-(1 6) glucosidase activity of debranching enzyme, releasing free glucose. Glucose
1-phosphate is converted to glucose 6-phosphate by phosphoglucomutase. In the muscle, glucose 6-phosphate
enters glycolysis. In the liver, the phosphate is removed by glucose 6-phosphatase, releasing free glucose that
can be used to maintain blood glucose levels at the beginning of a fast. A deficiency of the phosphatase causes
glycogen storage disease Type 1a (Von Gierke disease). This disease results in an inability of the liver to provide
free glucose to the body during a fast. It affects both glycogen degradation and gluconeogenesis. Glycogen syn-
thesis and degradation are reciprocally regulated to meet whole-body needs by the same hormonal signals,
namely, an elevated insulin level results in overall increased glycogenesis and decreased glycogenolysis,
whereas an elevated glucagon (or epinephrine) level causes increased glycogenolysis and decreased glycoge-
nesis . Key enzymes are phosphorylated by a family of protein kinases, some of which are cAMP-dependent (a
compound increased by glucagon and epinephrine). Phosphate groups are removed by protein phosphatase-1
(activated when insulin levels are elevated). Glycogen synthase, phosphorylase kinase and phosphorylase are
also allosterically regulated to meet tissues needs. In the well-fed state, glycogen synthase is activated by glu-
cose 6-phosphate, but glycogen phosphorylase is inhibited by glucose 6-phosphate, as well as by ATP. In the
liver, glucose also serves an an allosteric inhibitor of glycogen phosphorylase. The Ca2+ released from the endo-
plasmic reticulum in muscle during exercise and in liver in response to epinephrine activates phosphorylase
kinase by binding to the enzyme’s calmodulin subunit. This allows the enzyme to activate glycogen phosphory-
lase, thereby causing glycogen degradation.

M e ta bol ic cha r acter is ti cs R e gu l at io n

occurs
mainly in Regulated enzymes
Liver, muscle Glycogen

Cytosol occurs in UDP-Glucose

requires Glucose 6-P
UTP Glucose 1-P

Glycogen synthase
Well-fed state Fasting state
Glycogen phosphorylase
Ingestion of glucose
Ingestion of food
leads to leads to leads to
leads to
Blood glucose
leads to leads to Blood glucose
leads to dephosphorylation ATP phosphorylation
Glucose 6-P leads to
Glucose
Release of insulin Release of glucagon (liver) Release of insulin
AMP
(muscle) Release of glucagon
leads to leads to
Conversion Conversion
Protein phosphatase of glycogen of glycogen
to glucose to glucose Protein kinase
activity activity

Figure 11.13
Key concept map for glycogen metabolism in liver. [Note: Glycogen phosphorylase is phosphorylated by
phosphorylase kinase, the “b” form of which can be activated by Ca2+.]