Metabolism of GlycogenMetabolism of Glycogen

Glycogen is stored in cytoplasm

Structure of glycogen

α-1,4

α-1,6

Degradation of glycogen g g y g(glycogenolysis)

Glycogen phosphorylaseGlycogen phosphorylase • Glycogen (n) + Pi G-1-P + Glycogen (n-1)

• Glycogen phosphorylase

The removal of the the branch point glucose p gresidues requires the action of debranching enzyme which contains 2 activities:enzyme which contains 2 activities:

1) glucotransferase [oligo-(α-1,4→α-1,4)-glucantransferase];g ];

2) glucosidase [the amylo-α-(1,6) glucosidase].

Glycogen phosphorylase

• The glucose-1-phosphate produced by the action of glycogen phosphorylase is converted to glucose-6-phosphate by phosphoglucomutase.

Phosphoglucomutase• G-1-P G-6-P

OCH2O

HH

OH H

HOCH2OH

HH

OH H OPO

H

2-

PO32-

OHH

OH

OH

HOHOH

H

OH

OH

H OPO32

Glucose-1-phosphate Glucoses-6-phosphate

• Because liver is the main regulator of blood Glc level, liver cells contain a hydrolytic enzyme glucose-6-phosphatase that enables Glc to leave that organ.phosphatase that enables Glc to leave that organ.

Glucose- 6-phosphatase• G-6-P Glc + Pi

Gl S h iGlycogen Synthesis –Gl iGlycogenesis

• Synthesis of glycogen from α-D-glucose is i d b hcarried out by the enzyme glycogen synthase

Glycogen synthase substrates:the UDP gl cose;- the UDP-glucose;

- the non-reducing end of glycogen or glycogenin

First, glucose has to be phosphorylated:

hexokinase phosphoglucomutaseGlc G-6-P G-1-P

• A fragment of glycogen can serve as a primer in cells whose glycogen stores are not totaly depletedglycogen stores are not totaly depleted.

When glycogen stores are totaly depleted:totaly depleted:

• Elongation of a glycogen chain involves transfer of Glc from UDP glucose and making the α 1 4 linkages infrom UDP-glucose and making the α-1,4 linkages in glycogen by glycogen synthase:

Formation of branches of glycogen

Th 1 6 b h i l• The α-1,6 branches in glucose are produced by the branching enzyme.

Regulation of Glycogen SynthesisRegulation of Glycogen Synthesis and Degradationg

• In the liver glycogen synthesis accelerates during g y g y gperiods, when the body has been well fed, whereas glycogen degradation accelerates during periods g y g g g pof fasting.

• In skeletal muscle glycogen degradation occurs during active exercise and accumulation begins asduring active exercise and accumulation begins as soon as muscle is again at rest.

Regulation of glycogen synthesis and degradation isRegulation of glycogen synthesis and degradation is accomplished in 2 levels:

I. Glycogen synthase and glycogen phosphorylase are ll t i l t ll dallostericaly controlled.– In the well fed state glycogen synthase is allosterically

activated by G 6 P when it is present in elevatedactivated by G-6-P, when it is present in elevated concentrations.

– In contrast glycogen phosphorylase is allosterically– In contrast, glycogen phosphorylase is allosterically inhibited by G-6-P, as well as by ATP.

– Muscle glycogen phosphorylase is active in the presence ofMuscle glycogen phosphorylase is active in the presence of high AMP concentration, as occur in the muscle under extreme conditions of anoxia and ATP depletion.

II. Reversible phosphorylation of glycogen phosphorylase and glycogen synthase

• Glycogen synthase exists in 2 forms:Glycogen synthase exists in 2 forms: - a – not phosphorylated and active,

b h h l t d i ti- b – phosphorylated, inactive.

• Glycogen phosphorylase exists in 2 forms: - a – phosphorylated, active;- b non phosphorylated inactive- b – non phosphorylated, inactive.

• Reversible phosphorylation of both enzymes,glycogen phosphorylase and glycogen synthase, is regulated by hormones y , g yepinephrine, glucagone and insulin. These hormones induce the cascade of reactionshormones induce the cascade of reactionsresulting in phosphorylation of the enzymes.

cAMP-directed pathway (Livercells):

Insulin – increases glycogenesis by g y g yincreasing activity of glycogen synthase but the mechanism is unknown.

• In skeletal muscle cells. • The cascade is the result of

epinephrine binding to p p greceptors on the surface of muscle cells.

• Muscle cells lack glucagon g greceptors.

Regulation of Glycogen Synthesis and DegradationDegradation

glucagon, epinephrineAMP

g g , p pcAMP cAMP

Glycogen Glycogen synthaseGlycogen phosphorylase

Glycogen synthase

G 6 P

insulin

G-6-PG-6-PATP insulin

Glycogen storage deseasesGlycogen storage deseases (Glycogenoses)

• They are caused by genetic defects that result in deficiencies in certain enzymes of glycogen metabolism

(Glycogenoses)

deficiencies in certain enzymes of glycogen metabolism.

• These deficiencies lead to excessive accumulation of• These deficiencies lead to excessive accumulation of glycogen and/or the inability to use that glycogen as a fuel source.source.

Glycogen storage deseasesGlycogen storage deseases

T 0 (d fi i f • Type V ( deficiency of• Type 0 (deficiency of glycogen synthase in the liver) symptoms:

• Type V ( deficiency of glycogen phosphorylase in muscles), symptoms: liver), symptoms:

hypoglycemia, failure to thrive, early death.

Exercise-induced muscular pain, cramps, progressive weakness sometimes with

• Type I (deficiency of

weakness, sometimes with myoglobinuria.

yp ( yglucose 6-phosphatase), symptoms: enlarged liver

d kid f ti

• Type VII ( deficiency of PFK in muscle and RBC), symptoms: as in the type Vand kidney, fasting

hypoglycemia, acidosis.symptoms: as in the type V, in addition hemolysis (burst of RBC).