INTEGRATED BASIC SCIENCES

MODULE 11 | METABOLISM OF CARBOHYDRATES MARCH| 2024

METABOLISM OF GLYCOGEN • muscle glycogen does not directly yield free glucose
BIOMEDICAL IMPORTANCE (lacks glucose-6-phosphatase)
glycogen o pyruvate formed by glycolysis in muscle can
• major storage carbohydrate in animals undergo transamination to alanine, w/c is
• corresponding to starch in plants exported from muscle and used for glu-
• branched polymer of α-D-glucose coneogenesis in liver

• occurs mainly in liver & muscle Glycogen storage diseases

o w/ modest amounts in brain • group of inherited disorders characterized by:
✓ deficient mobilization of glycogen
• liver content > muscle ✓ deposition of abnormal forms of glycogen
o BUT muscle mass of body > liver ‘.’ ¾ of total
body glycogen is in muscle • = liver damage and muscle weakness
o some result in early death

highly branched structure of glycogen

• provides a large # of sites for glycogenolysis
o ‘.’ permit rapid release of glucose-1-phosphate
for muscle activity

endurance athletes
muscle glycogen • require a slower, more sustained release of glucose-
• provides readily available source of glucose-1- 1-phosphate
phosphate for glycolysis w/in muscle itself • formation of branch points in glycogen is slower than
addition of glucose units to a linear chain
liver glycogen • some practice carbohydrate loading
• reserve to maintain blood glucose concentration in o exercise to exhaustion (muscle glycogen in
fasting state largely depleted) followed by high-
carbohydrate meal
after meal: ▪ = rapid glycogen synthesis, w/ fewer
o 450 mmol/L glucose equivalents branch points than normal

after overnight fast:

o falling to about 200 mmol/L

after 12-18 hrs fasting:

o almost totally depleted

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INTEGRATED BASIC SCIENCES
MODULE 11 | METABOLISM OF CARBOHYDRATES MARCH| 2024
GLYCOGENESIS OCCURS MAINLY IN MUSCLE & glycogen synthase
LIVER • catalyzes formation of glycoside bond between:
GLYCOGEN BIOSYNTHESIS INVOLVES UDP- o C-1 of glucose of UDPGlc
GLUCOSE o C-4 of terminal glucose residue of glycogen
in glycolysis = liberating UDP
• glucose phosphorylated to glucose- 6-phosphate by:
o hexokinase in muscle • addition of glucose residue to preexisting glycogen
o glucokinase in liver chain, or “primer” occurs @ nonreducing, outer
end of molecule
• glucose-6-phosphate isomerized to glucose-1- o branches of glycogen molecule become
phosphate by phosphoglucomutase elongated as successive 1 → 4 linkages are
o enzyme itself is phosphorylated, and phosphate formed
group takes part in reversible reaction w/c
glucose 1,6-bisphosphate is an
intermediate

• glucose-1-phosphate reacts w/ uridine triphosphate

(UTP)
forming:
✓ active nucleotide uridine diphosphate
glucose (UDPGlc)
✓ pyrophosphate

The biosynthesis of glycogen.

BRANCHING INVOLVES DETACHMENT OF

EXISTING GLYCOGEN CHAINS
• growing chain at least 11 glucose residues long
o branching enzyme transfers part of 1 → 4
chain (at least 6 glucose residues) to
neighboring chain to form a 1 → 6 linkage
▪ establishing branch point

• branches grow by further additions of 1 → 4-

glucosyl units and further branching.
catalyzed by UDPGlc pyrophosphorylase.
o reaction proceeds in direction of UDPGlc
GLYCOGENOLYSIS IS NOT THE REVERSE OF
formation GLYCOGENESIS, BUT IS A SEPARATE PATHWAY
▪ because pyrophosphatase catalyzes glycogen phosphorylase
hydrolysis of pyrophosphate to 2 × • catalyzes rate-limiting step in glycogenolysis:
phosphate o phosphorolytic cleavage of 1 → 4 linkages of
▪ ‘.’ removing one of reaction products glycogen
▪ = glucose-1-phosphate
o has low Km for glucose-1-phosphate

o present in relatively large amounts

▪ ‘.’ not regulatory step in glycogen
synthesis

initial steps in glycogen synthesis

• involve protein glycogenin
o 37-kDa protein glucosylated on specific
tyrosine residue by UDPGlc

glycogenin
• catalyzes transfer of further 7 glucose residues from
UDPGlc, in 1 → 4 linkage
o = glycogen primer [substrate for glycogen
synthase]

• remains @ core of glycogen granule

Steps in glycogenolysis

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INTEGRATED BASIC SCIENCES
MODULE 11 | METABOLISM OF CARBOHYDRATES MARCH| 2024
• different isoenzymes of glycogen phosphorylase in • reaction catalyzed by phosphoglucomutase
liver, muscle, and brain, encoded by different genes o reversible
• glycogen phosphorylase requires pyridoxal o glucose-6-phosphate can be formed from
phosphate as coenzyme glucose- 1-phosphate

AA METABOLISM PHOSPHORYLASE • in liver, but not muscle

o glucose-6-phosphatase catalyzes hydrolysis
reactive group: aldehyde catalytically active: of glucose-6-phosphate
of coenzyme phosphate group
✓ = glucose exported
✓ = increase in blood glucose concentration
• terminal glucosyl residues from outermost chains
of glycogen molecule ▪ lumen of smooth ER
o removed sequentially until ~4 glucose residues ▪ genetic defects of G6P transporter can
remain on either side of 1 → 6 branch cause variant of type I glycogen
storage disease
• debranching enzyme has 2 catalytic sites in a
single polypeptide chain • glycogen granules can also be engulfed by
o 1: glucan transferase lysosomes
▪ transfers trisaccharide unit from one o where acid maltase catalyzes hydrolysis of
branch to the other glycogen to glucose
▪ expose 1 → 6 branch point o important in glucose homeostasis in
neonate.
o 2: 1,6-glycosidase o genetic lack of lysosomal acid maltase causes
▪ catalyzes hydrolysis of 1 → 6-glycoside type II glycogen storage disease
bond to liberate free glucose
• lysosomal catabolism of glycogen is under hormonal
o further phosphorylase action can then proceed control

• combined action of phosphorylase and other

enzymes = complete breakdown of glycogen

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INTEGRATED BASIC SCIENCES
MODULE 11 | METABOLISM OF CARBOHYDRATES MARCH| 2024
CYCLIC AMP INTEGRATES REGULATION OF
GLYCOGENOLYSIS & GLYCOGENESIS
• principal enzymes controlling glycogen metabolism
o glycogen phosphorylase
o glycogen synthase

• enzymes regulated in opposite directions by

allosteric mechanisms and covalent modification by
reversible phosphorylation and dephosphorylation of
enzyme protein
o response to hormone action

phosphorylation of:

glycogen phosphorylase glycogen synthase

increased activity reduced activity

• phosphorylation is increased in response to cyclic

AMP (cAMP)
o formed from ATP by adenylyl cyclase at inner
surface of cell membranes in response to hor-
mones: epinephrine, norepinephrine, and
glucagon.

o hydrolyzed by phosphodiesterase
▪ ‘.’ terminate hormone action

• liver: insulin increases activity of

phosphodiesterase

GLYCOGEN PHOSPHORYLASE REGULATION IS Formation and hydrolysis of cyclic AMP (3′,5′-adenylic acid,
DIFFERENT IN LIVER & MUSCLE cAMP)

ROLE OF GLYCOGEN • 5′ AMP acts as potent signal of energy state of

in liver in muscle muscle cell
o formed as concentration of ADP increase
provide source of
(indicate need for increased substrate
provides free glucose for glucose- 6-phosphate
export to maintain blood for glycolysis in response metabolism to permit ATP formation)
concentration of glucose to need for ATP for muscle ▪ as a result of reaction of adenylate kinase:
contraction • 2 × ADP ↔ ATP + 5′ AMP

both tissues, enzyme is: CAMP ACTIVATES GLYCOGEN PHOSPHORYLASE

• activated by phosphorylation phosphorylase kinase

o catalyzed by phosphorylase kinase (yield • activated in response to cAMP
phosphorylase a)
• increased concentration of cAMP activates cAMP-
• inactivated by dephosphorylation dependent protein kinase
o catalyzed by phosphoprotein phosphatase o w/c catalyzes phosphorylation by ATP of
(yield phosphorylase b) inactive phosphorylase kinase b to active
phosphorylase kinase a
in response to hormonal and other ▪ in turn, phosphorylates phosphorylase b
signals to phosphorylase a

• there is instantaneous overriding of hormonal in liver:

control • cAMP is formed in response to glucagon
o secreted in response to falling blood glucose
• active phosphorylase a in both tissues:
o allosterically inhibited by ATP & glucose-6- • muscle is insensitive to glucagon
phosphate o signal for increased cAMP formation is
norepinephrine, secreted in response to fear
• in liver, but not muscle: or fright, when there is a need for increased
o free glucose is also an inhibitor glycogenolysis to permit rapid muscle
activity.
• muscle phosphorylase differs from liver isoenzyme
in having binding site for 5′ AMP
o acts as allosteric activator of (inactive)
dephosphorylated b-form of enzyme.

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INTEGRATED BASIC SCIENCES
MODULE 11 | METABOLISM OF CARBOHYDRATES MARCH| 2024

CA2+ SYNCHRONIZES ACTIVATION OF GLYCOGEN GLYCOGENOLYSIS IN LIVER CAN BE CAMP-

PHOSPHORYLASE W/ MUSCLE CONTRACTION INDEPENDENT
• glycogenolysis in muscle increases 100-fold at onset in liver: cAMP-independent activation of glycoge-
of contraction nolysis
• same signal (increased cytosolic Ca2+) is • response to stimulation of α1 adrenergic receptors
responsible for initiation of both contraction & [epinephrine & norepinephrine]
glycogenolysis
• involves mobilization of Ca2+ into cytosol
• muscle phosphorylase kinase o followed by stimulation of Ca2+/calmodulin-
o activates glycogen phosphorylase sensitive phosphorylase kinase
o tetramer of 4 different subunits: α, β, γ, and δ
• also activated by vasopressin, oxytocin, &
α and β subunits angiotensin II acting either through:
o contain serine residues phosphorylated by o calcium
cAMP-dependent protein kinase o phosphatidylinositol bisphosphate pathway

δ subunit PROTEIN PHOSPHATASE-1 INACTIVATES

o identical to Ca2+-binding protein calmodulin GLYCOGEN PHOSPHORYLASE
o binds 4 Ca2+ • phosphorylase a & phosphorylase kinase a
o dephosphorylated & inactivated by protein
• binding of Ca2+ activates catalytic site of γ phosphatase-1
subunit even while enzyme is in dephosphorylated
b state • protein phosphatase-1
o inhibited by a protein, inhibitor-1
• phosphorylated a form ▪ active only after phosphorylated by cAMP-
o only fully activated in presence of high dependent protein kinase
concentrations of Ca2+
o ‘.’ cAMP controls both activation and
inactivation of phosphorylase

• Insulin reinforces effect by inhibiting activation

of phosphorylase b
o indirectly by increasing uptake of glucose
o = increased formation of glucose-6-phosphate,
inhibitor of phosphorylase kinase

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INTEGRATED BASIC SCIENCES
MODULE 11 | METABOLISM OF CARBOHYDRATES MARCH| 2024

ACTIVITIES OF GLYCOGEN SYNTHASE & • dephosphorylation of glycogen synthase b

PHOSPHORYLASE ARE RECIPROCALLY REGULATED o carried out by protein phosphatase-1
• different isoenzymes of glycogen synthase in liver, ▪ under control of cAMP-dependent protein
muscle, and brain phosphorylase kinase
o glycogen synthase
▪ exists in both phosphorylated and GLYCOGEN METABOLISM IS REGULATED BY A
nonphosphorylated states BALANCE IN ACTIVITIES BETWEEN GLYCOGEN
▪ effect of phosphorylation is reverse of that SYNTHASE & PHOSPHORYLASE
in phosphorylase • as phosphorylase is activated by rise in
concentration of cAMP (via phosphorylase kinase)
• active glycogen synthase a = dephosphorylated o glycogen synthase is converted to inactive
• inactive glycogen synthase b = phosphorylated form
o both effects mediated via cAMP-dependent
• 6 different protein kinases act on glycogen protein kinase
synthase
o at least 9 different serine residues in ‘.’ inhibition of glycogenolysis enhances net
enzyme that can be phosphorylated glycogenesis
‘.’ inhibition of glycogenesis enhances net
• 2 of protein kinases: glycogenolysis
o Ca2+/ calmodulin dependent (one is
phosphorylase kinase) • protein phosphatase-1 w/ broad specificity
accounts for dephosphorylation of:
o cAMP-dependent protein kinase ✓ phosphorylase a
▪ allows cAMP-mediated hormone action to ✓ phosphorylase kinase
inhibit glycogen synthesis synchronously ✓ glycogen synthase b
w/ activation of glycogenolysis
o protein is inhibited by cAMP-dependent
• insulin also promotes glycogenesis in muscle at protein kinase via inhibitor-1
same time as inhibiting glycogenolysis
o by raising glucose-6-phosphate concentrations,
w/c stimulates dephosphorylation & activation
of glycogen synthase

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INTEGRATED BASIC SCIENCES
MODULE 11 | METABOLISM OF CARBOHYDRATES MARCH| 2024
• ‘.’ glycogenolysis can be terminated and • secondary phosphorylations
glycogenesis can be stimulated, or vice versa, o modify sensitivity of primary sites to
synchronously phosphorylation & dephosphorylation
o as both processes are dependent on activity of (multisite phosphorylation)
cAMP-dependent protein kinase o also allow insulin, by increased glucose- 6-
phosphate, to act reciprocally to those of cAMP
• both phosphorylase kinase and glycogen synthase
may be reversibly phosphorylated at > 1 site by
separate kinases and phosphatases