Download Glycogen Metabolism

Pentose Phosphate Pathway
Where the ribose comes from?
• The pentose phosphate pathway is an alternate route for
the oxidation of glucose.
Used for nucleic
acid synthesis
Reactions of the pentose phosphate
pathway occur in the cytosol in two phases
• 1st phase
Glucose 6-phosphate + 2 NADP++ H2O
ribose 5-phosphate + CO2 + 2 NADPH + 2 H+
• 2nd phase
The pentose phosphates are recycled back to glucose 6phosphate. Overall, 6 five-carbon sugars are converted to 5
six-carbon sugars.
Overview
• Function
– NADPH production
• Reducing power carrier
– Synthetic pathways
• Role as cellular antioxidants
– Ribose synthesis
• Nucleic acids and
nucleotides
1st phase: NADPH producing reactions
1.
2.
3.
Glucose-6-P dehydrogenase
Lactonase
6-P-gluconate dehydrogenase
2nd phase:
1. Epimerase; 2. Isomerase 3. Transketolase 4. Transaldolase
5. Phosphohexose isomerase
Ru–5-P: ribulose-5-P; X-5-P: xylulose-5-P; R-5-P: ribose -5-P
Used for nucleic
acid synthesis
Regulation
• Glucose-6-P dehydrogenase
(G6PDH)
– First step
– Rate limiting
– Feedback inhibited by
NADPH
– Induced by insulin
Role of NADPH in the RBC
• Production of superoxide
– Hb-Fe2+-O2 -> Hb-Fe3+ + O2-.
• Spontaneous reaction
• O2-. + 2H+ > 2H2O2
• Both O2-. & H2O2 can damage cell membranes, and
cause hemolysis
Glycine – cycteine - glutamate
G6PDH Deficiency and Hemolytic Anemia
• One of the most common genetic diseases
– 4 hundred variants of G6PDH deficiency
– Mediterranean, Asian, African descent
• 400 million people affected worldwide
• 10-14% of African-American men with G6PD
deficiency
G6PDH Deficiency and Hemolytic Anemia
• The chemicals known to increase oxidant stress
– Primaquine and quinine (anti-malarial drug)
– Sulfonamides (antibiotic)
– Asprin
– Quinadine
– Naphthalene
– Fava beans
Exposure to these chemicals results in
increased cellular production of superoxide
and hydrogen peroxide
Glycogen Metabolism
Liver Cell
Glucose is stored as glycogen predominantly in liver
and muscle cells.
Glycogen is a polymer of glucose residues
linked by
 a(14) glycosidic bonds, mainly
 a(16) glycosidic bonds, at branch points.
Glycogen catabolism
(breakdown)
Glycogen phosphorylase catalyzes phosphorolytic cleavage
of the a(14) glycosidic linkages of glycogen, releasing
glucose-1-phosphate as reaction product.
glycogen(n residues) + Pi 
glycogen (n–1 residues) + glucose-1-phosphate
Phosphorylase can cleave a(14) linkages only to within 4
residues of a branch point.
This is called a "limit branch".
Debranching enzyme has 2 enzyme actives:
Transferase
a-1,6-glucosidase
The transferase transfers 3 glucose residues from a 4-residue
limit branch to the end of another branch, reducing the limit
branch to a single glucose residue.
transferase
 The a-1,6-glucosidase catalyzes hydrolysis of the
a(16) linkage, yielding free glucose. This is a minor
fraction of glucose released from glycogen.
Phosphoglucomutase catalyzes the reversible reaction:
glucose-1-phosphate  glucose-6-phosphate
Glycogen
Glucose-1-P
Glucose
Hexokinase or Glucokinase
Glucose-6-Pase
Glucose-6-P
Glucose + Pi
Glycolysis
Pathway
Pyruvate
Glucose metabolism in liver.
Glucose-6-phosphate may (mainly in liver) be dephosphorylated
by glucose-6-phosphotase for release into the blood.
glucose-6-phosphate + H2O  glucose + Pi
Most other tissues lack this enzyme.
Glycogen synthesis
UDP-glucose pyrophosphorylase
Uridine diphosphate glucose (UDP-glucose) is the
immediate precursor for glycogen synthesis.
Glycogenin initiates glycogen synthesis.
• Glycogenin is an enzyme that catalyzes attachment of a glucose
molecule to one of its own tyrosine residues.
• Glycogenin is a dimer, and evidence indicates that the 2 copies of the
enzyme glucosylate one another.
Tyr
active site
active site
Tyr
Glycogenin dimer
Glycogenin catalyzes glucosylation (UDP-glucose as the donor) to
yield an O-linked disaccharide with a(14) glycosidic linkage.
This is repeated for second glucose added.
Glycogen Synthase then catalyzes elongation of glycogen chains
initiated by Glycogenin.
A branching enzyme transfers a segment from the end of a glycogen
chain to the C6 hydroxyl of a glucose residue of glycogen to yield a
branch with an a(16) linkage.
Regulation of glycogen metabolism
• Regulating site for glycogen synthesis
Glycogen synthase
• Regulating site for glycogen catabolism
Glycogen phosphorylase
Glycogen Phosphorylase
 AMP activates Phosphorylase
 ATP & glucose-6-phosphate inhibit Phosphorylase
 Thus glycogen breakdown is inhibited when ATP and glucose6-phosphate are plentiful.
Glycogen Synthase
 Activated by glucose-6-P (opposite of effect on Phosphorylase).
Thus Glycogen Synthase is active when high blood glucose leads to
elevated intracellular glucose-6-P.
Regulation by hormones
Glucagon and epinephrine:
• Inhibit glycogen synthase
• Activate glycogen phosphorylase
• Increase glycogen catabolism and increase blood glucose
Insulin:
• Inhibit glycogen phosphorylase
• Activate glycogen synthase
• Increase glycogen synthesis and decrease blood glucose
Hormone (epinephrine or glucagon)
via G Protein (Ga-GTP)
Adenylate cyclase
(inactive)
Adenylate cyclase
(active)
catalysis
ATP
cyclic AMP + PPi
Activation
Phosphodiesterase
AMP
Protein kinase A
(inactive)
Protein kinase A
(active)
ATP
ADP
Phosphorylase kinase
(b-inactive)
Phosphatase
Phosphorylase kinase (P)
(a-active)
ATP
Pi
ADP
Phosphorylase
(b-allosteric)
Phosphorylase (P)
(a-active)
Phosphatase
Pi
Regulation of Glycogen Phosphorylase by Hormones
Regulation of Glycogen Synthase by Hormones
Glycogen Function
• In liver – The synthesis and breakdown of glycogen is
regulated to maintain blood glucose levels.
• In muscle - The synthesis and breakdown of glycogen is
regulated to meet the energy requirements of the
muscle cell.