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THE PENTOSE PHOSPHATE PATHWAY

THE PENTOSE PHOSPHATE PATHWAY. Dr Sumreena Mansoor Assistant Professor Biochemistry Shifa college of Medicine. OBJECTIVES.

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THE PENTOSE PHOSPHATE PATHWAY

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  1. THE PENTOSE PHOSPHATE PATHWAY Dr Sumreena Mansoor Assistant ProfessorBiochemistry Shifa college of Medicine

  2. OBJECTIVES • To understand the function of the pentose phosphate pathway in production of NADPH and ribose precursors for nucleic acid synthesis • To examine the importance of NADPH in protection of cells against highly reactive oxygen species • To relate defects in the pentose phosphate pathway to disease conditions.

  3. PENTOSE PHOSPHATE PATHWAY • The pentose phosphate pathway is an alternate route for the oxidation of glucose

  4. FUNCTIONS 1- Generates(NADPH) for fat & steroid biosynthesis 2- Generates pentoses and pentose Phosphates 3- Provides catabolic path for dietary pentose metabolism 4- Generates aldose and ketose families of C3, C4, C5, and C7 carbohydrates

  5. PENTOSE PHOSPHATE PATHWAY • Two Irreversible Oxidative reactions • Reversible sugar-Phosphate Interconversion • No ATP directly consumed or produced in the cycle • NADP+ is used as hydrogen acceptor CO2 • Glucose-6-Phosphate 2NADPH(OXIDATIVE PART)

  6. TWO PHASES • OXYDATIVE • 2 irreversible reactions • NADPH • NON- OXYDATIVE • Series of reversible reactions • Ribose-5-phosphate----Nucleotide Biosynthesis • (Diet, Degradation of structural CHO HMP act as mechanism for metabolic use of 5-Carbon sugars

  7. IRREVERSIBLE OXIDATIVE REACTIONS Glucose-6-Phosphate Ribulose 5-phosphate+Co2+2NADPH • IMPORTANCE OF IRREVERSIBLE OXIDATIVE REACTIONS • NADPH dependent Fatty acid synthesis-----liver, lactating mammary gland • NADPH-dependent biosynthesis of Steroid----- Testes, Ovaries, Placenta, Adrenal cortex • R. B. C requires------- NADPH for Glutathione reduction

  8. Glucose-6-phosphate NADP+ GLUCOSE-6-PHOSPHATEDEHYDROGENASE NADPH+H+ (G6PD) (-)NADPH (+)INSULIN C=O HC-OH HO-CH O HC-OH HC CH2O P 6-phosphogluconate OXIDATIVE PHASE

  9. 6-Phosphogluconate NADP+6-PHOSPHOGLUCONATEDEHYDROGENASE NADPH+H+= (OXIDATIVE DECARBOXYLATION FROM C-1) CO2 CH2OH C=O HCOH HCOH CH2OP D-ribulose-5-phosphate(5C-ketose)

  10. REVERSIBLE NON-OXIDATIVE REACTIONS • Occur in all cell----- RNA, DNA • Interconversion of 3,4,5,6 & 7 C-sugars • Ribulose 5-phosphate Ribose 5-P Nucleotide Synthesis Fructose 6-P HMP Shunt Isomerase More NADPH demand in reductivereactions Glycolysis Intermediates Trans-ketolase (2-C) Trans-aldolase (3-C) Glyceraldehyde 3-P Glycolysis Trans Iso Fructose 6-P Glyceraldehyde 3-P Erthrose 4-P Sedoheptulose 7-P Xylulose 5-P Ribulose 5_P More RIBOSE demand for Nucleotide synthesis RIBOSE 5-P epimerase

  11. SUMMARY • Glucose-6- P + 2 NADP+ + H2O • Ribose-5- P +CO2 + 2 NADPH + 2H+ • This reductive portion of the shunt • has generated • NADPH • 5-carbon sugars

  12. NADPH • Reductive Biosynthesis • Reduction of H2O2 • Cytochrome P450 • Phagocytosis by white blood cells • Synthesis of nitric oxide

  13. REACTIVE OXYGEN SPECIES (ROS)

  14. R B C Glucose 6-P • Oxidant Stress • Infection • Drugs • fava beans HMP Shunt NADPH NADP+ G6PD Glutathione Reductase Pentose Phosphate Oxidized Glutathione Reduced Glutathione O2 H2O2 Glutathione Peroxidase (Se) If accumulates O2 + H2O Hb Denaturation (Heinz bodies) Membrane Damage (Hemolytic Anemia)

  15. ROLE OF NADPH AND GLUTATHIONE IN PROTECTING CELLS AGAINST ROS

  16. CYTOCHROME P450

  17. CYTOCHROME P450

  18. NEUTROPHIL---KILLING BACTERIA Neutrophil granulocytes have trapped Shigella bacteria. Neutrophil Extracellular Traps (NETs) that are composed of nucleic acid and aggressive enzymes

  19. CHRONIC GRANULOMATOUS DISEASE

  20. SYNTHESIS OF NO

  21. G6PD • Rare • Hemolytic Anemia

  22. G6PD DEFICIENCY • ROS---- damage protein, lipid in cell • HB----------Denature Protein Oxid of SH (Heinz Bodies) • Lipid Peroxidation ----Hemolysis

  23. ACUTE EPISODIC HEMOLYSIS • RBC cannot synthesize new proteins, the ENZYME is lost over time and RBC lyse • ACCELERATED • Drugs • Fava beans • Infection

  24. GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY CAUSES HEMOLYTIC ANEMIA • Mutations present in some populations causes a deficiency in glucose 6-phosphate dehydrogenase, with consequent impairment of NADPH production • Detoxification of H2O2 is inhibited, and cellular damage results - lipid Peroxidation leads to erythrocyte membrane breakdown and hemolytic anemia. • Most G6PD-deficient individuals are asymptomatic

  25. REGULATION OF PENTOSE PHOSPHATE PATHWAY • The entry of glucose 6-phosphate into the pentose phosphate pathway is controlled by the cellular concentration of NADPH • NADPH is a strong inhibitor of glucose 6-phosphate dehydrogenase • As NADPH is used in various pathways, inhibition is relieved, and the enzyme is accelerated to produce more NADPH

  26. THANKS

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