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Lec07 hm ppath


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Lec07 hm ppath

  1. 1. Berg • Tymoczko • Stryer Biochemistry Sixth Edition Chapter 20:The Calvin Cycle and the Pentose Phosphate Pathway Copyright © 2007 by W. H. Freeman and Company
  2. 2. Hexose MonophosphatePentose Phosphate Pathway Glycolysis, TCA, and oxidative phosphorylation are primarily concerned with the generation of ATP. The PPP meets the need of all organisms for a source of NADPH to use in reductive biosynthesis. The reducing power is NADPH. There is a fundamental distinction NADH  NADPH The direction of HMP depends on the supply and demand forintermediates in the cycle…
  3. 3. Structure ofnicotinamidederived e carriers• In NAD+, R = H• In NADP+, R = PO3-
  4. 4. Two Major Functions1. NADPH2. RiboseOverall reaction:3G-6-P + 6NADP+  3CO2 + 2G-6-P + Glyceraldehyde-3P + 6NADPH + 6H+ It occurs in the cytosol because NADP+ is used as a hydrogen acceptor.There are two sequential reactions. 1. Oxidative 2. Nonoxidative
  5. 5. Oxidative and Nonoxidative Reactions  In oxidative, G-6-P undergoes dehydrogenation and decarboxylation to give a pentose ribulose-5-P.  In nonoxidative, ribulose 5-P is converted back to G-6-P by a series of reactions involving two enzymes 1. Transketolase 2. Transaldolase  Dehydrogenation of G-6-P is the major biological control of the HMP.  G-6-PD is strongly inhibited by NADPH.
  6. 6. Oxidative Branch
  7. 7. Non-oxidative Branch
  8. 8. Ribose-5-P + Xylulose-5-P  Transketolase, TPP Sedoheptulane-7-P + Glyceraldehyde-3-P2C unit----- transferred by transketolaseThis 2-C moiety is bound to TPP first then transferred.Two products of transketolase then enter another reaction knownas transaldolation.3C unit---- transferred by transaldolaseSedoheptulase-7-P + Glyceraldehyde-3-P  Transaldolase  F-G-P + Erythrope-4-P
  9. 9. Another transketolase reaction: ‒ X-5-P + E-4-P  Transketolase  G-3-P + F-6-P ‒ X-5-P serves as a donor of “active glycoaldehyde”.Therefore, at the end of PPP: ‒ NADPH  ‒ Ribose-5-P  ‒ Glyce 3-P and Fructose-6-P  GlyThe differences between glycolytic pathway and PPP are: ‒ NADPH ‒ CO2 ‒ ATP ‒ Ribose-5-P for nucleotide synthesis
  10. 10.  The PPP is much more active in adipose tissue than in muscle. It is important in tissues such as adipose, liver, mammary gland, and adrenal cortex (NADPH depended synthesis of steroids). Transketolase that is defective in TPP binding can cause a neuropsychiatric disorder. • Wernicke-Korsakoff Syndrome ‒ Lack of TPP in susceptible people ‒ Paralysis of eye movements ‒ Abnormal gait ‒ Decreased mental function ‒ Severely impaired memory ‒ Transketolase from patients with the Wernicke-Korsakoff syndrome binds thiamine PP ten times less than does the enzyme from normal persons
  11. 11. The flow of Glc-6-P dependson the need for NADPH, ribose 5-P, and ATP  Mode 1 • Much more ribose 5-P is needed than NADPH • It is seen in rapidly dividing cells • The stoichiometry of mode 1 is:  5 Glc 6-P + ATP  6 ribose 5-P + ADP + H+  Mode 2 • The needs for NADPH = ribose 5-P are balanced. • Formation of 2 NADPH and 1 Ribose 5-P • The stoichiometry of mode 2 is:  Glc6-P + 2NADP+ + H2O  ribose 5-P + 2NADPH + 2H+ CO2
  12. 12. Continue on modes Mode 3 • Much more NADPH than ribose 5-P is required. For example adipose tissue requires a high level of NADPH for the synthesis of fatty acids. – Glc6-P is completely oxidized to CO2 – 3 reactions are active • Oxidative phase forms 2 NADPH and 1 Ribose 5-P • Ribose 5-P  F-6-P and Glyceraldehyde 3-P • Glc6-P is made from F-6-P and Glyceraldehyde 3-P The sum of the mode 3 reaction is: • (The stoichiometry of mode 3) is: Glc6-P + 12NADP+ + 7H2O  6CO2 + 12 NADPH + 12H++ Pi Therefore Glc6-P can be completely oxidized to CO2 with the generation of NADPH
  13. 13. Continue on modes Mode 4 – Both NADPH and ATP are required. – Ribose 5-P  pyruvate, F-6-P and glyceraldehyde 3-P – These enter glycolytic pathway The stoichiometry of mode 4 is:3 Glc6-P + 6 NAD+ + 5 Pi + 8 ADP  5 pyruvate + 3CO2 + 6 NADPH + 5 NADH + 8 ATP + 2 H2O + 8 H+ – Pyruvate can be oxidized more!
  14. 14. G-6-P dehydrogenase deficiency G-6-P dehydrogenase deficiency causes a drug induced hemolytic anemia. An antimalarial drug primaquine was introduced in 1926. Some patients developed severe symptoms like: • Jaundice • Hb decrease • Massive destruction of red blood cells • Death In 1956, the basis of drug induced hemolytic anemia was elucidated The primary defect is a deficiency in G-6-P dehydrogenase in red blood cells.
  15. 15. Role of NADPH in RBCs GSSG  GSH by glutathione reductase, which requires NADPH. GSH keeps Cys residues in hemoglobin and other RBC proteins in the reduced state. Normally, the ratio of the GSH/GSSG  500 in RBCs Electrons are transferred by NADPH to FAD first on the reductase, then to a S-S bridge between 2 Cys residues in the enzyme subunit, and finally to GSSG. GSH + ROOH  GSSG + H2O + ROH Cells with low GSH are more susceptible to hemolysis because ROOH eliminated by GSH preoxidase by using GSH as a reducing agent.
  16. 16. Glutathione reductase
  17. 17. Cells with low GSH Cells with low GSH are more susceptible to hemolysis when fava beans are eaten. In some regions where malaria is endemic (the middle east) fava beans are a staple food. They are known to contain two beta glycosieds – Vicine – Convicine They oxidize GSH! Individuals who eat fresh fava beans are protected to a certain extent from malaria. A condition known as favism results when some Glc 6-P deficient individuals develop a severe hemolytic anemia after ingestion of fava beans.
  18. 18. More about Glc 6-P dehydrogenase deficiency In the absence of G-6-P dehydrogenase, Hb can no longer be maintained in the reduced form. Hb molecules then cross-link with one another to form aggregates called Heinz bodies on cell membranes. Membranes damaged by the Heinz bodies and ROS (reactive Oxygen Species) become deformed and the cell undergos LYSIS  Hemolytic anemia!
  19. 19. The light micrograph showsRBC obtained from a persondeficient in Glc 6-Pdehydrogenase. The darkdots represent Hb aggregates.RBCs in such people lyse ifthere is oxidative stress(an increase in ROS)
  20. 20. Adeficiency of Glc 6-P dehydrogenase confers anevolutionary advantage in some circumstances 11% of African-Americans have this deficiency. This suggest that this deficiency may indeed be useful under certain environmental conditions. In fact, deficiency of Glc 6-P dehydrogenase protects against malaria! How?? – In order for the parasites (Plasmodium Falciparum) to survive, GSH is needed and products of PPP are also needed for optimal growth!!! – Thus, Glc 6-P dehydrogenase deficiency is a mechanism of protection against malaria, which accounts for its high frequency in malaria- infested regions of the world. WE SEE HERE ONCE AGAIN THE INTERPLAY OF HEREDITY AND ENVIRONMENT IN THE PRODUCTION OF DISEASE!