glycogen: similar to starch,

but branched polysaccharide

glycogen phosphorylase (dimeric)
cleaves 1→ 4 glycosidic bonds

uses inorganic phosphate

Contains PLP (vitamin B6 derivative)
does not utilize ATP (in vitro reversible)
a separate enzyme is
needed for debranching
glycogen phosphorylase

debranching: two different

enzymatic activities
makes a linear polymer debranching enzyme
4 α-D-glucanotransferase

debranching enzyme
amylo α-1,6-glycosidase
phosphoglucomutase G-1-P → G-6-P isomerization

glucose-1-phosphate glucose-1,6-bisphosphate glucose-6-phosphate

liver : (glucose-6-phosphatase) glucose-6-phosphate + H2O → glucose + Pi2-

lactate
muscle: G-6-P
CO2
II type glycogen storage disease (Pompe disease)

α-1,4 glucosidase deficiency

lysosomes cannot degrade glycogen granules

other glycogen metabolic pathways are active

heart failure and breathing problems

hexokinase
glucokinase
1. Hexokinase/glucokinase: Glucose→ Glucose-6-phosphate
2. Phosphoglucomutase: Glucose-6-phosphate→ ← Glucose-1-phosphate
3. Glucose-1-phosphate uridylyltransferase:
Glucose-1-phosphate + UTP→ UDP-Glucose + PPi 4-
hydrolysis of inorganic phosphate PPi 4- + H2O → 2 Pi 2-
(energetically favorable)
4. Glycogen synthase Uracil
UDP
glycogen synthase
Uracil

UDP-glucose [glucose]n-1 [glucose]n

5. Nucleoside diphosphate kinase

UDP+ ATP→
← UTP + ADP
α-1,4-glycosidic bond
α-1,6-glycosidic bond

α-1,4-glycosidic bond
pre-requisite:

At least 11 unit long strand with 1→4 linkage

Branching enzyme cleaves 7 (6-8) long strand
and attaches it to an existing strand with a
1→6 linkage
107 Da glycogen would be equivalent to ~400mM glucose concentration
glucose is osmotically active
this can only be compensated by pumping out other osmotically active compounds or
intake of large amount of water

slower to mobilize
requires oxygen for energy production
Most part of the fatty acids cannot be converted to glucose and contribute to
regulation of blood sugar levels (but glycerol and propionyl-CoA are gluconeogenesis
substrates!)

a straight polymer could have only 1 non-reducing end

degradation and synthesis would be significantly slower
osmotically less active
The KM of glycogen synthase is only low for glycogen of large
molecular weight
affinity decreases with decreasing size,
thus glucose cannot serve as primer
The primer is a protein called glycogenin.
It functions in a dimeric form.
The one single reducing end of the glycogen (the anomeric
carbon of the very first glucose which is the
original aldehyde group) is attached to
the tyrosine 194 of the glycogenin.
H&E and PAS staining in muscle
Impaired skeletal muscle, cardiac muscle, and liver functions
REGULATION OF GLYCOGENOLYSIS

cAMP

ATP

ATP, AMP
cAMP
allosteric regulators
ADP
cAMP ATP ADP
secondary messenger

glucagon, epinephrine, insulin AMP

hormones → modulate ATP

kinase activity

glucagon, epinephrine: activate glycogenolysis

insulin: inhibits glycogenolysis
cAMP
REGULATION OF GLYCOGENOLYSIS

cAMP

ATP

ADP
ATP ADP
Glycogen phosphorylase a
active
AMP

Glycogen phosphorylase b ATP

inactive

cAMP
REGULATION OF GLYCOGENOLYSIS

Phosphorylation of glycogen phosphorylase changes the structure of the enzyme

Phosphorylation in general modulates conformation of the active loops

REGULATION OF GLYCOGENOLYSIS

cAMP

Glycogen phosphorylase a
active ATP

phosphorylase kinase a

ADP
ATP ADP

Glycogen phosphorylase b
AMP
inactive
ATP
AMP stimulates
phosphoprotein phosphatase

cAMP
REGULATION OF GLYCOGENOLYSIS

cAMP

Glycogen phosphorylase a
active ATP

phosphorylase kinase a
protein kinase A
ADP
phosphoprotein phosphatase ADP
ATP

Glycogen phosphorylase b
AMP
inactive
ATP
AMP stimulates
phosphoprotein phosphatase

cAMP
REGULATION OF GLYCOGENOLYSIS

Phosphorylase kinase

Ca2+ binding to calmodulin

activates phosphorylase kinase

glycogenolysis

tetramer, the delta subunit is calmodulin

calmodulin is a Ca2+ sensitive regulatory protein

calmodulin
REGULATION OF GLYCOGENOLYSIS

Glycogen phosphorylase b cAMP

inactive
phosphoprotein phosphatase ATP

ADP
ATP ADP
inhibition of phosphoprotein phosphatase
facilitates phosphorylase a formation
AMP
activates glycogenolysis
ATP

hormonal regulation:
glucagon, epinephrine activates
insulin inhibits
cAMP
REGULATION OF GLYCOGENOLYSIS
 Glucagon and epinephrine:

cAMP concentration increases

cAMP inhibits phosphoprotein phosphatase

facilitates phosphorylase a formation +

epinephrine is a β agonist
epinephrine binds to α-adrenergic receptors
and activates Phospholipase C

secondary messengers are formed

from PIP2
PKC
PIP2: phosphatidylinositol 4,5 bisphosphate

IP3: inositol 1,4,5 triphosphate

diacylglicerol

Ca2+ release, activation of

phosphorylase kinase (calmodulin subunit)
 epinephrine binds to β-adrenergic receptors
cAMP is formed

cAMP inhibits phosphoprotein phosphatase

PKA

helps formation of phosphorylase a

glycogenolysis is activated

fructose 2,6 bisphosphate

PFK-1 is activated
glycolysis is activated
nerve impulse induces Ca 2+ release

protein kinase
and phosphorylase is activated

glycogenolysis is activated
REGULATION OF GLYCOGEN SYNTHASE

glycogen synthase

85kDa homotetramer, 9 different sites for phosphorylation, ~11 kinases involved

 +
pyruvate

Insulin activates phosphoprotein phosphatase and inhibits glycogen degradation, while activates its synthesis
enzymes regulated by acetylation are marked by red
 degradation of peroxides

C5 compounds: ATP, CoA, NAD, FAD, RNA, DNA

3. C3, C4, C6, C7 compounds

glycolysis intermediates
 NADP+ NADPH

oxidation

ring opening

Glucose-6-phosphate-dehydrogenase
catalyzes the first, committed step of pentose-
phosphate pathway
availability of NADP+ regulates

NADP+
oxidative
decarboxylation NADPH

ketose-aldose
isomerisation
 NADP+ NADPH

oxidation

ring opening

NAD+ : electron acceptor, oxidation of metabolites

NADPH : reducing agent used in most synthetic

pathways

NADP+
oxidative
decarboxylation NADPH

ketose-aldose
isomerisation

NAD+ and NADP+ redox properties are similar

differently used in catabolic and synthetic pathways
 reversible reactions
ketose-aldose
isomerisation
enediol intermediates

glucose-6-phosphate + 2NADP+ +H2O ←

→
ribose-5-phosphate + 2NADPH + 2H+ + CO2

oxidative phase

nucleotide synthesis epimerisation

(different
stereoisomer)
NONOXIDATIVE PHASE OF PENTOSE PHOSPHATE PATHWAY

Intermediates can be used in glycolysis

TPP cofaktor

thiamine
pyrophosphate

C2 transfer
transketolase
2 C5 C3 + C7
NONOXIDATIVE PHASE OF PENTOSE PHOSPHATE PATHWAY

2 C5 C3 + C7

transketolase
TPP cofactor
glycolysis intermediates
C2 transfer

C5 + C4 C3 + C6

transketolase
TPP cofactor
 NONOXIDATIVE PHASE OF THE PENTOSE PHOSPHATE PATHWAY

2 xilulose-5-phosphate + ribose-5-phosphate 2 fructose-6-phosphate +

glyceraldehide-3-phosphate
3 ribose-5-phosphate

intermediates of nucleic acid degradation intermediates of glycolysis

 3
sum
-phosphate
Nonoxidative phase

glycolysis
intermediates

Low rate of pentose-phosphate

pathway, not much direct glucose
oxidation
 Glucose
glucokinase +ATP
Glucose-6-phosphate
+
+ATP
Fructose-1,6-bisphosphate

Dihydro
ACTIVATION OF GALACTOSE
Selectins

Inflammation
Lactase enzyme deficiency leading to abdominal discomfort after milk sugar
consumption.

Liver aldolase B deficiency, fatal disease if fructose free diet is not maintained.

Liver fructokianse deficiency, benign condition.

 due to the ATP deficiency

due to the ATP deficiency

DIABETES MELLITUS
Type 1 diabetes, insulin-dependent, early-onset: autoimmune destruction
of pancreatic β-cells. The subsequent lack of insulin leads to increased
blood and urine glucose. The classical symptoms are polyuria, polydipsia,
polyphagia and weight loss.
Type 2 diabetes, insulin-independent, adult-onset: metabolic disorder,
insulin resistant, decreased insulin sensitivity. Common symptoms include
high blood sugar, insulin resistance, relative lack of insulin, increased thirst,
frequent urination, and unexplained weight loss.

adipose tissue
muscle
Insulin is an anabolic hormone: fatty acid synthesis, glycogen snthesis, and protein synthesis

GLUT 4 glucose transporter (muscle, adipose tissue) is insulin dependent, insulin increases
transporter number on cell surface.

Insulin enhances glycolysis in the liver by enhancing glucokinase, PFK-I and pyruvate kinase
expression (in diabetes decreased glycolysis).
Insulin blocks gluconeogenesis by inhibiting PEPCK and G-6-Pase transcription (in diabetes
enhanced gluconeogenesis).

Insulin inhibits glycogenolysis by activating PP-1 and cAMP phosphodiesterase (PDE). The PP-1
directly dephosphorylates glycogen phosphorylase a, reforming the inactive glycogen
phosphorylase b. The phosphodiesterase converts cAMP to AMP. This activity removes the
second messenger (generated by glucagon and epinephrine) and inhibits PKA. In this manner,
PKA can no longer cause the phosphorylation cascade that ends with formation of (active)
glycogen phosphorylase a.
Enhances glycogen synthesis. Glycogen synthase is active in dephosphorylated state, insulin
activates glycogen synthase via PP1. . In diabetic patients the rate of glycogen synthesis
decreases.