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 + + H 2 O  ribose 5-phosphate + CO 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 phase 1st phase: NADPH producing reactions 1.Glucose-6-P dehydrogenase 2.Lactonase 3.6-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-Fe 2+ -O 2 -> Hb-Fe 3+ + O 2 -. Spontaneous reaction O H + > 2H 2 O 2 Both O 2 -. & H 2 O 2 can damage cell membranes, and cause hemolysis

Glycine – cycteine - glutamate

G 6 PDH 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   (1  4) glycosidic bonds, mainly   (1  6) glycosidic bonds, at branch points.

Glycogen phosphorylase catalyzes phosphorolytic cleavage of the  (1  4) glycosidic linkages of glycogen, releasing glucose-1-phosphate as reaction product. glycogen (n residues) + P i  glycogen (n–1 residues) + glucose-1-phosphate Glycogen catabolism (breakdown)

Phosphorylase can cleave  (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

Glucose-6-phosphate may (mainly in liver) be dephosphorylated by glucose-6-phosphotase for release into the blood. glucose-6-phosphate + H 2 O  glucose + P i Most other tissues lack this enzyme.

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.

Glycogenin catalyzes glucosylation (UDP-glucose as the donor) to yield an O-linked disaccharide with  (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  (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 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

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.