Pentose Phosphate Pathway<br />Generation of NADPH and Pentoses<br />
Overview<br />Function<br />NADPH production<br />Reducing power carrier<br />Synthetic pathways<br />Role as cellular ant...
Characteristics:Tissue Distribution<br />Demand for NADPH<br />Biosynthetic pathways<br />FA synthesis (liver, adipose, ma...
Characteristics:Oxidative and Non-oxidative Phases<br />Oxidative phases<br />Reactions producing NADPH<br />Irreversible ...
NADPH producing reactions<br />Glucose-6-P dehydrogenase<br />6-P-gluconate dehydrogenase<br />
The Pentose Phosphate Pathway:Non-oxidative phases<br />
Regulation<br />Glucose-6-P dehydrogenase<br />First step<br />Rate limiting<br />Allosteric Regulation<br />Feedback inhi...
Role of NADPH in the RBC<br />Production of superoxide<br />Hb-Fe2+-O2 -&gt; Hb-Fe3+ + O2-.<br />Spontaneous rxn, 1% per h...
Detoxification of Superoxide Anion and Hydrogen Peroxide<br />Antioxidant enzymes<br />Superoxide dismutase<br />Glutathio...
Case Study<br />21 yo male medical student with malaria<br />Treated with primaquine<br />Four days later:<br />Black colo...
G6PDH Deficiency and Hemolytic Anemia<br />Most common genetic enzymopathy <br />400 hundred variants of G6PDH deficiency<...
Worldwide distribution of G6PD deficiency: 1995<br />
G6PD Deficiency<br />Distribution of G6PD deficiency coincides prevalence of malaria<br />G6PD deficiency may impart some ...
Genetics<br />Recessive sex-linked mutation<br />X-chromosome<br />Rare in females (two X-chromosomes)<br />Homozygous mut...
Inheritance of G6PD Deficiency<br />
G6PD Deficiency<br />Exposure to anti-malarial drugs (Primaquine) results in increased cellular production of superoxide a...
Fava Beans<br />Grown worldwide<br />Important in Middle East<br />High in protein<br />Frost resistant perennial<br />Gen...
Case Study<br />21 yo male medical student with malaria<br />Treated with primaquine<br />Four days later:<br />Black colo...
Symptoms <br />Black colored urine<br />Hemolysis may result in urinary excretion of hemoglobin<br />Low RBC count & low h...
RBCs with Heinz Bodies<br />Precipitation of hemoglobin due to disulfide bond formation between Hb molecues<br />Upper pho...
Elevated Reticulocytes<br />A RBC containing granules or filaments representing an immature stage in cell development<br /...
Defective G6PDH<br />Results in enzyme with unstable structure<br />Patient with 10% of normal activity<br />Enough to gen...
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Pentose Phosphate Pathway

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Pentose Phosphate Pathway

  1. 1. Pentose Phosphate Pathway<br />Generation of NADPH and Pentoses<br />
  2. 2. Overview<br />Function<br />NADPH production<br />Reducing power carrier<br />Synthetic pathways<br />Role as cellular antioxidants<br />Ribose synthesis<br />Nucleic acids and nucleotides<br />
  3. 3. Characteristics:Tissue Distribution<br />Demand for NADPH<br />Biosynthetic pathways<br />FA synthesis (liver, adipose, mammary)<br />Cholesterol synthesis (liver)<br />Steroid hormone synthesis (adrenal, ovaries, testes)<br />Detoxification (Cytochrome P-450 System) – liver<br />Reduced glutathione as an antioxidant (RBC)<br />Generation of superoxide (neutrophils)<br />
  4. 4. Characteristics:Oxidative and Non-oxidative Phases<br />Oxidative phases<br />Reactions producing NADPH<br />Irreversible <br />Non-oxidative phases<br />Produces ribose-5-P<br />Reversible reactions feed to glycolysis<br />
  5. 5. NADPH producing reactions<br />Glucose-6-P dehydrogenase<br />6-P-gluconate dehydrogenase<br />
  6. 6. The Pentose Phosphate Pathway:Non-oxidative phases<br />
  7. 7. Regulation<br />Glucose-6-P dehydrogenase<br />First step<br />Rate limiting<br />Allosteric Regulation<br />Feedback inhibited by NADPH<br />Inducible enzyme<br />Induced by insulin<br />
  8. 8. Role of NADPH in the RBC<br />Production of superoxide<br />Hb-Fe2+-O2 -&gt; Hb-Fe3+ + O2-.<br />Spontaneous rxn, 1% per hour<br />O2-. + 2H2O -&gt; 2H2O2<br />Both O2-. & H2O2 can produce reactive free radical species, damage cell membranes, and cause hemolysis<br />
  9. 9. Detoxification of Superoxide Anion and Hydrogen Peroxide<br />Antioxidant enzymes<br />Superoxide dismutase<br />Glutathione peroxidase<br />Glutathione reductase<br />
  10. 10. Case Study<br />21 yo male medical student with malaria<br />Treated with primaquine<br />Four days later:<br />Black colored urine<br />Low RBC count<br />Elevated reticulocyte count<br />RBC with Heinz bodies<br />Low hemoglobin<br />Elevated serum bilirubin<br />Pt recovered in a few days<br />
  11. 11. G6PDH Deficiency and Hemolytic Anemia<br />Most common genetic enzymopathy <br />400 hundred variants of G6PDH deficiency<br />Mediterranean, Asian, African descent<br />400 million people affected worldwide<br />50% of Kurdish men<br />10-14% of African-American men with G6PD deficiency<br />
  12. 12. Worldwide distribution of G6PD deficiency: 1995<br />
  13. 13. G6PD Deficiency<br />Distribution of G6PD deficiency coincides prevalence of malaria<br />G6PD deficiency may impart some degree of malaria resistance<br />Also sickle cell anemia<br />
  14. 14. Genetics<br />Recessive sex-linked mutation<br />X-chromosome<br />Rare in females (two X-chromosomes)<br />Homozygous mutation: <br />high hemolysis and anemia<br />Heterozygous mutation: <br />Normally asymptomatic <br />unless exposed to drugs (primaquine, anti-malarial drug) or compounds (fava bean) that produce superoxide or hydrogen peroxide<br />
  15. 15. Inheritance of G6PD Deficiency<br />
  16. 16. G6PD Deficiency<br />Exposure to anti-malarial drugs (Primaquine) results in increased cellular production of superoxide and hydrogen peroxide (Primaquine sensitivity)<br />Other chemicals known to increase oxidant stress<br />Sulfonamides (antibiotic)<br />Asprin and NSAIDs<br />Quinadine and quinine<br />Napthlane (mothballs)<br />Fava beans (vicine & isouramil)<br />
  17. 17. Fava Beans<br />Grown worldwide<br />Important in Middle East<br />High in protein<br />Frost resistant perennial<br />Genetically modified fava bean being developed<br />Low in vicine and isouramil<br />Favism<br />
  18. 18. Case Study<br />21 yo male medical student with malaria<br />Treated with primaquine<br />Four days later:<br />Black colored urine<br />Low RBC count<br />Elevated reticulocyte count<br />RBC with Heinz bodies<br />Low hemoglobin<br />Elevated serum bilirubin<br />Pt recovered in a few days<br />
  19. 19. Symptoms <br />Black colored urine<br />Hemolysis may result in urinary excretion of hemoglobin<br />Low RBC count & low hemoglobin<br />Result of high rate of hemolysis<br />Elevated bilirubin<br />Catabolism of heme <br />
  20. 20. RBCs with Heinz Bodies<br />Precipitation of hemoglobin due to disulfide bond formation between Hb molecues<br />Upper photo shows distorted RBCs with large Heinz bodies<br />Bottom photo shows RBC stained with methylene blue<br />
  21. 21. Elevated Reticulocytes<br />A RBC containing granules or filaments representing an immature stage in cell development<br />Normally constitutes 1% of circulating RBCs<br />Reticulocytosis<br />Elevation of reticulocytes<br />Indicative of active erthropoiesis in red bone marrow<br />
  22. 22. Defective G6PDH<br />Results in enzyme with unstable structure<br />Patient with 10% of normal activity<br />Enough to generate NADPH under normal condition<br />Newly made RBCs have normal 6PDH activity<br />Patients recover quickly (8 days)<br />
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