Oxidation of Pyruvate to Acetyl-CoA
Pyruvate formed in the cytosol transported into
the mitochondrion
Oxidatively decarboxylated to acetyl-CoA
NADH produced, transferred to the respiratory
chain.
o 1 mol glucose  2 mol NADH ~ 2 x 2,5 ATP
o Enzyme : Pyruvate Dehydrogenase complex
o Pyruvate dehydrogenase component inhibited by
NADH and Acetyl-CoA.
o Deficiency of B1 vitamin  beri-beri
Pyruvate is decarboxylated by the pyruvate
dehydrogenase component of the enzyme complex
to a hydroxyethyl derivative of the thiazole ring of
enzyme-bound thiamin diphosphate, which in turn
reacts with oxidized lipoamide, the prosthetic group
of dihydrolipoyl transacetylase, to form acetyl
lipoamide (Figure 18–5).
Acetyl lipoamide reacts with coenzyme A to form
acetyl-CoA and reduced lipoamide. The reaction is
completed when the reduced lipoamide is reoxidized by
a flavoprotein, dihydrolipoyl dehydrogenase,
containing FAD. Finally, the reduced flavoprotein is
oxidized by NAD+ , which in turn transfers reducing
equivalents to the respiratory chain.
Pyruvate + NAD+ + CoA  Acetyl-CoA + NADH + H+ +
CO
Pyruvate dehydrogenase
Pyruvate Dehydrogenase Is Regulated by
End-Product Inhibition & Covalent Modification
Pyruvate dehydrogenase is inhibited by its products,
acetyl-CoA and NADH.
It is also regulated by phosphorylation by a kinase of
three serine residues on the pyruvate dehydrogenase
component of the multi enzyme complex, resulting in
decreased activity and by dephosphorylation by a
phosphatase that causes an increase in activity.
The kinase is activated by increases in the
[ATP]/[ADP], [acetyl-CoA]/[CoA], and [NADH]/[NAD+ ]
ratios.
Thus, pyruvate dehydrogenase, and therefore
glycolysis, is inhibited both when there is adequate
ATP available, and also when fatty acids are being
oxidized.
Glycogen: Glycogenesis & glycogenolysis
 Energy storage as carbohydrate in the
liver and muscle
 In the liver up to 6 % w/w
 In the muscle up to 4 % w/w
 Fasting for 18 hours will depletes
glycogen in the liver
 In the muscle glycogen will never be
depleted
 Molecular mass up to 4 millions
Glycogenesis
 In the fed state, glycogen synthesis increase
 Glucose 6P (some, not all)  G 1P
(phosphoglucomutase)
 G 1P with UTP  UDPG + PP
(UDPG pyrophosphorylase)
 PP  Pi drives the reaction to the right
(pyrophosphatase)
 UDPG + glycogenn  glycogenn+1 + UDP
(Glycogen Synthase = GS)
 UDP + ATP  UTP + ADP
 Glycogen synthesis from glucose require
two ATP
Pathways of glycogenesis and of glycogenolysis in the liver.
Amylo α(1-4) α(1-6)
Transglucosidase)
Pathways of glycogenesis and of glycogenolysis in the liver.
Glycogenolysis
During fasting(liver) or during contraction (muscle)
 Glycogen cleavaged by phosphorylase and
debranching enzymes
 Glucose 1P ( G 1P ) and glucose are released
 Phosphate Pi is required
 In the liver : G 1P  G 6P (phosphogluco mutase)
G 6P  G + Pi (glucose 6Pase)
 In the muscle : G 1P  G 6P
(phosphogluco mutase)
G 6P enter glycolysis  ATP
Glucose 6 Pase can only be found in the liver,
intestine and kidney
Amylo α(1-4) α(1-4) Glucantransferase
Control of Glycogenolysis
During fasting when blood glucose tend
to decline, glucagon through protein G
will activates adenylyl cyclase.
Adenylyl cyclase catalyzes formation of
cAMP from ATP.
cAMP in turn activates cAMP
Dependent Protein Kinase. Then it
catalyzes Phosphorylase Kinase
into PK-P
Phosphorylase Kinase-P (active = a)
will catalyzes Phosphorylase
(b=inactive) to Phosphorylase-P (a).
The Phosphorylase-P will split
Glycogen. Glucose 1P released
(require Pi). Glucose 6 phosphatase
hydrolysis G 6P to G and Pi.
Glucose enter the blood stream to
stabilize blood Glucose.
Epinephrine in muscle
If you are startled epinephrine in muscle
activates Adenylyl cyclase , catalyze ATP  cAMP
cAMP Dependent PK  active. Phosphorylase
kinase  active.
Phosphorylase  active. Glycogen  G 1P.  G 6P
 no G 6Pase in the muscle, G 6P  x G.
G 6P  glycolysis  ATP
Eye  Central N.S  Peripheral nerves  Synapses 
Ca++
Ca/Calmodulin  phosphorylase kinase active etc.
Role of Ca++ in glycogenolysis
Glycogenesis
Gycogen Synthase ( GS ) active form GS, and GS-P
inactive form.
Protein Kinase
 GS-P
↑
GSK
There are seven Protein kinase that control
glycogenesis
Ca++ / Calmodulin Dependent ( 1 phosphorylase
kinase )
cAMP Dependent Protein kinase
Glycogen Synthase Kinase (GSK) 3, 4 and 5
GS
Glycogenolysis in muscle increases several 100-fold at
the onset of contraction; the same signal (increased
cytosolic Ca2+ ion concentration) is responsible for
initiation of both contraction and glycogenolysis. Muscle
phosphorylase kinase, which activates glycogen
phosphorylase, is a tetramer of four different subunits,
α, β, γ, and δ. The α and β subunits contain serine
residues that are phosphorylated by cAMP-dependent
protein kinase. The δ subunit is identical to the Ca2+ binding protein calmodulin, and binds four Ca2+ . The
binding of Ca2+ activates the catalytic site of the
subunit even while the enzyme is in the
dephosphorylated b state; the phosphorylated a form is
only fully activated in the presence of high
concentrations of Ca2+ .
Protein Phosphatase-1
Protein Phosphatase-1 hydrolyzes protein-P to Protein Kinase
and Pi .
Enzymes - P :
 Glycogen Synthase-P
 Phosphorylase-P
 Phosphorylase Kinase-P
Protein Phosphatase-1 is inhibited by Inhibitor 1-P
Inhibitor 1  Inhibitor 1-P its phosphorylation catalyzed by
cAMP Dependent PK.
The Control of Phosphorylase Differs
between Liver & Muscle
In the Liver:
Inhibited by
ATP
G 6P
Glucose
In the muscle :
Inhibited by:
ATP
G 6P
Activated by 5’AMP
Effect of Insulin:
Phosphorylase is inhibited by glucose
(in the liver) .
Insulin inhibits Phosphorylase if G
available.
If glucose concentration increases
G 6P follows, in turn it will activates
glycogen synthase
Insulin  (+) GS-P  GS
Protein phosphatase-1
Epinephrine effects liver glycogenolysis
through :
1.Its effects on glucagon released
2.Beta-adrenergik receptor, in turn
cAMP formation etc.
3.Alfa-adrenergic receptor
Inositol triphosphate (IP3),  Ca++
exit from ER  Phosphorylase kinase 
phosphorylase etc.
( The major mechanism of the three)
Glycogen Storage Diseases Are Inherited
Type Ia glycogenosis ( von Gierke's disease ).
Deficiency : glucose-6 phosphatase
Clinical features :
Glycogen accumulation in liver and renal tubule cells,
hypoglycemia; lactic acidemia; ketosis; hyperlipemia.
Type V (Myophosphorlylase deficiency,
McArdle's syndrome)
Deficiency : Muscle phosphorylase
Poor exercise tolerance; muscle glycogen
abnormally high (2.5–4%); blood lactate very
low after exercise
Type VI (Hers' disease)
Deficiency : Liver phosphorylase
Clinical features:
Hepatomegaly;
accumulation of glycogen in liver;
mild hypoglycemia;
generally good prognosis
Type VII (Tarui's disease)
Deficiency : Muscle and erythrocyte
phosphofructokinase 1
Clinical features:
Poor exercise tolerance; muscle glycogen abnormally high (2.5–4%);
blood lactate very low after exercise;
also hemolytic anemia