1. Pentose phosphate pathway ط Two phases of the pathway : oxidative and interconversion phase ط Significance of PMP shunt in certain tissues ط Production of NADPH ++ H + and ribose-5-Phosphate ط Glucose-6-phosphate Dehydrogenase deficiency and hemolytic anemia D4 336-41

2. Introduction 1. G6P ==> Glycolysis (energy) Glycogenesis (storage) Pentose Phosphate Pathway (biosynthesis, cell integrity) 2. PPP (or Hexose Monophosphate Shunt) occur in cytosol through oxid & nonoxid phases: - Oxid. phase produce 1CO2, 2NADPH, 1Pentose Phosphate (RL5P) - nonoxid. phase produce glycolytic intermediates (2F6P, 1GAP) 3. Hexose => dehydrogenation => pentose (+NADPH/CO2) => transformation => other pentoses => rearrangement => Hexoses 4. ketose as donor & aldolase as acceptor

3. Reactions of PPP 1. Oxidative Phase fig8.1: G6P  G6PDH (+NADPH)  6PGL (6C lactone)  6GLH “lactonase” (–H2O)  6PG (6C gluconate)  6PGDH (+NADPH/CO2)  RL5P (5C)  RIsomerase “through an enediol intermediate”  R5P (5C) 2. Non-oxidative Phase (interconversion) fig8.2: RL5P (5C)  REpimerase  X5P (5C) R5P (5C) + X5P (5C)  Transkeolase  GAP (3C) + SHP (7C) GAP (3C) + SHP (7C)  Transaldolase  E4P (4C) + F6P (6C) E4P (4C) + X5P (5C)  Transketolase  F6P (6C) + GAP (3C)

4. Regulation of PPP (balance between cell need) 1. Oxidative Phase: 2. Non-oxidative Phase: a) If NADPH & R5P are balanced: G6P => oxidation => R5P => STOP - no non-oxid phase b) If NADPH is needed more: G6P => oxidation => R5P => Glycolytic Intermediate (glycolysis/gluconeogenesis) - Complete oxid of G6P to CO2 - Resynthesis of G6P from Ru5P - Prevents R5P accumulation, which inhibits NADPH synthesis c) If R5P is needed more: No oxidation => 3R5P <= 2F6P + 1GAP <= Glycolysis - Converts G6P to F6P & GAP then reverse reactions to form R5P * Balance between glycolysis & PPP to produce CO2 depends on metabolic requirement of the cell

5. Importance of PPP 1. Only source of Pentoses used in: - Nucleic Acid Synthesis (DNA, RNA) - Coenzyme as NAD+, FAD - Nucleotides as ATP - Rapidly dividing tissues with high - nucleotide synth (bone marrow, skin, gastric mucosa) - Cells utilizes large amount of NADPH

6. Importance of PPP 2. Major source of NADPH used for: A. Biosynthesis of: - FA (liver, AT, Lactating mammalian glands) - Steroids (testis, adrenal cortex) - Cholesterol (liver, adrenal cortex, skin, gonads) - Catecholamine (nervous system, adrenal medulla) * NADPH is not used in striated muscle to synthesise FA & steroids B. Preserve Lens transparency: - Maximum concentration of NADPH is required to preserve transparency Bacterialcidic action: - Protects against superoxides anions radicals (O2–) during bacterial killing by macrophages C. Preserve RBCs membrane integrity: figfig a) Serves as sulfhydryl buffer by maintaining ferrous iron (Fe2+) of Hb & prt of RBCs in reduced form through keeping glutathione in reduced form: Glutatione (oxid)  Reductase (–NADPH) è Glutathione (reduc) b) Increase cell life span by detoxification of peroxides (H2O2) and prevents formation of MetHb: Glutathione (reduc)  Peroxidase (–H2O2)  2 H2O

8. Summary of PPP · Glycolysis supplies ATP for membrane ion pump. PPP supplies NADPH to maintain reducing atmosphere in cells exposed to concentration of O2 radicals including RBCs, Lens and Cornea TableTable · PPP serves as mechanism of synthesis/degradation of other sugars than hexoses (erythroses, xyluloses, sedehetaploses) · Cells do not use PPP for energy production but for biosynthesis and protection

9. Table: Differences between Glucose Oxidation in Pentose Phosphate ShuntGlycolysis Occur in certain cells Coenzyme is NADP + / TPP No ATP formed 2 CO 2 produced 6 Pentoses are formed Oxidation is first step (direct pathway) Occur in all cells Coenzyme is NAD + 8 or 2 ATP are formed No CO 2 is produced No pentoses are formed Oxidation step is late (GAPDH)

10. Clinical Correlation of PPP cc.8.1 G6PDH deficiency is x-linked genetic defect · Deficiency lead to induced hemolystic anemia and maybe death, which can be induced by: o Oxidant drugs intake as anti-malarial (pamaquine & primaquine) o Ingestion of fava beans leading to a condition called Favism · Decrease in NADPH concentration, destruction of RBCs surface (hemolysis), Black urine, Jaundice, low Hb