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Pentose Phosphate Pathway
Where the ribose comes from?
Used for nucleic acid synthesis
• The pentose phosphate pathway is an alternate route for the oxidation of glucose.
Reactions of the pentose phosphate pathway occur in the cytosol in two phases
• 1st phase1st phase
Glucose 6-phosphate + 2 NADP++ H2Oribose 5-phosphate + CO2 + 2 NADPH + 2 H+
• 2nd phase
The pentose phosphates are recycled back to glucose 6-phosphate. 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 phase1st phase: NADPH producing reactions
1. Glucose-6-P dehydrogenase2. Lactonase3. 6-P-gluconate dehydrogenase
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
2nd phase:
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 (14) glycosidic bonds, mainly (16) glycosidic bonds, at branch points.
Glycogen phosphorylase catalyzes phosphorolytic cleavage of the (14) glycosidic linkages of glycogen, releasing glucose-1-phosphate as reaction product.
glycogen(n residues) + Pi
glycogen (n–1 residues) + glucose-1-phosphate
Glycogen catabolism (breakdown)
Phosphorylase can cleave (14) 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(16) 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
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 Glucose
Hexokinase or Glucokinase
Glucose-6-Pase Glucose-1-P Glucose-6-P Glucose + Pi Glycolysis Pathway
Pyruvate Glucose metabolism in liver.
Uridine diphosphate glucose (UDP-glucose) is the immediate precursor for glycogen synthesis.
Glycogen synthesis
UDP-glucose pyrophosphorylase
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 (14) 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 (16) 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 glucose-6-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 (G-GTP)
Adenylate cyclase Adenylate cyclase (inactive) (active) catalysis
ATP cyclic AMP + PPi
Activation Phosphodiesterase
AMP
Protein kinase A Protein kinase A (inactive) (active) ATP
ADP
Phosphorylase kinase Phosphorylase kinase (P) (b-inactive) (a-active) Phosphatase ATP
Pi ADP Phosphorylase Phosphorylase (P) (b-allosteric) (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.