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SEMINARS!!!!

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  1. SEMINARS!!!! Dr. Andy Baldwin, Department of Biochemistry, University of Toronto. Title: "The structure and dynamics of AlphaB-crystallin oligomers, determined using solution-state nuclear magnetic resonance spectroscopy, ion-mobility mass spectrometry and electron microscopy" F 3:15 pm.

  2. Exam R 6-8 pm Sl 110

  3. Regulation of Glycogen Metabolism!!

  4. GlygogenMuscle: 1-2%Liver: 10%!! Breakdown Synthesis

  5. Figure 15-28 G6 Phosphatase is located on ER membrane.

  6. Synthesis

  7. Nucleotide donors: formation irreversible good for enzyme recognition are excellent leaving groups

  8. Glycogenin catalyzes two distinct reactions. Initial attack by the hydroxyl group of Tyr194 on C-1 of the glucosyl moiety of UDP-glucose results in a glucosylated Tyr residue. The C-1 of another UDP-glucose molecule is now attacked by the C-4 hydroxyl group of the terminal glucose, and this sequence repeats to form a nascent glycogen molecule of eight glucose residues attached by (α1→4) glycosidic linkages.

  9. Glycogenin structure.Muscle glycogenin (Mr 37,000) forms dimers in solution. The substrate, UDP-glucose, is bound to a Rossmann fold near the amino terminus and is some distance from the Tyr194 residues—15 Å from the Tyr in the same monomer, 12 Å from the Tyr in the dimeric partner. Each UDP-glucose is bound through its phosphates to a Mn2+ ion that is essential to catalysis. Mn2+ is believed to function as an electron-pair acceptor to stabilize the leaving group, UDP. The glycosidic bond in the product has the same configuration about the C-1 of glucose as the substrate UDP-glucose, suggesting that the transfer of glucose from UDP to Tyr194 occurs in two steps. The first step is probably a nucleophilic attack by Asp162, forming a temporary intermediate with inverted configuration. A second nucleophilic attack by Tyr194 then restores the starting configuration

  10. Glycogenin and the structure of the glycogen particle. (b) Structure of the glycogen particle. Starting at a central glycogenin molecule, glycogen chains (12 to 14 residues) extend in tiers. Inner chains have two (α1→6) branches each. Chains in the outer tier are unbranched. Particles consist of about 55,000 glucose residues in a molecule of about 21 nm diameter and Mr ~1 × 107.

  11. Regulation of muscle glycogen phosphorylase by covalent modification.

  12. Cascade mechanism of epinephrine and glucagon action.

  13. Figure 18-22 The enzymatic activities of phosphorylase a and glycogen synthase in mouse liver in response to an infusion of glucose. Page 648

  14. Figure 18-9 The control of glycogen phosphorylase activity. Page 635

  15. Figure 18-13 Control of glycogen metabolism in muscle. Page 639

  16. Figure 18-16 X-Ray structure of rat testis calmodulin. Page 642

  17. Figure 18-19 Schematic diagram of the Ca2+–CaM-dependent activation of protein kinases.

  18. Figure 18-21 The antagonistic effects of insulin and epinephrine on glycogen metabolism in muscle. Page 645

  19. Maintaining Blood Glucose Levels • During exercise or long after meals, the liver releases glc into the bloodstream • Glc inhibits pancreatic -cells from secreting glucagon. Inhibition is released when glc levels fall. • Glucagon receptors on liver cells respond to glucagon binding by activating AC causing  [cAMP]. •  [cAMP] increases the rate of glycogen breakdown and increased G6P. • G6P cannot pass through cell membranes. However, the liver, which doesn’t rely on glc for a major energy source, has a G6P hydrolase to release glc.

  20. Figure 18-24 Formation and degradation of -D-fructose-2,6-bisphosphate as catalyzed by PFK-2 and FBPase-2. Page 649

  21. Figure 18-26a The liver’s response to stress. (a) Stimulation of -adrenoreceptors by epinephrine activates phospholipase C to hydrolyze PIP2 to IP3 and DAG. Page 652

  22. Figure 18-26b The liver’s response to stress. (b) The participation of two second messenger systems. Page 652

  23. Effects of glycogen synthase kinase 3 (GSK3) on glycogen synthase activity.

  24. Phosphatidylinositol 3-kinase (PI-3K) converts phosphatidylinositol 4,5-bisphosphate (PIP2) in the membrane to phosphatidylinositol 3,4,5-trisphosphate (PIP3). insulin receptor substrate-1 (IRS-1) glycogen synthase kinase 3 (GSK3) phosphoprotein phosphatase 1 (PP1)

  25. The glycogen-targeting protein GM is one of a family of proteins that bind other proteins (including PP1) to glycogen particles.

  26. Glycogen phosphorylase of liver as a glucose sensor.

  27. FIGURE 15-36 (part 1) Glycogen phosphorylase of liver as a glucose sensor. Glucose binding to an allosteric site of the phosphorylase a isozyme of liver induces a conformational change that exposes its phosphorylated Ser residues to the action of phosphorylase a phosphatase (PP1). This phosphatase converts phosphorylase a to phosphorylase b, sharply reducing the activity of phosphorylase and slowing glycogen breakdown in response to high blood glucose. Insulin also acts indirectly to stimulate PP1 and slow glycogen breakdown.

  28. FIGURE 15-36 (part 2) Glycogen phosphorylase of liver as a glucose sensor. Glucose binding to an allosteric site of the phosphorylase a isozyme of liver induces a conformational change that exposes its phosphorylated Ser residues to the action of phosphorylase a phosphatase (PP1). This phosphatase converts phosphorylase a to phosphorylase b, sharply reducing the activity of phosphorylase and slowing glycogen breakdown in response to high blood glucose. Insulin also acts indirectly to stimulate PP1 and slow glycogen breakdown.

  29. LEHNINGER PRINCIPLES OF BIOCHEMISTRY Fifth Edition David L. Nelson and Michael M. Cox CHAPTER 16 The Citric Acid Cycle © 2008 W. H. Freeman and Company

  30. Pyruvate Dehyrdogenase Reaction: Pyruvate + Coenzyme A + NAD+ Acetyl CoA + CO2 + NADH TCA Cycle : AcetylCo A + 3 NAD+ + FAD + GDP + Pi 2 CO2 + 3 NADH + FADH2 + GTP + CoA

  31. PDH complex Figure 17-3a

  32. Figure 21-4 Structural organization of the E. coli PDC. Even more complex in yeast and mammals! 12 dihydrolypoyl dehydrogenase (E3) (as dimers) 24 subunits Page 769 PDH: 24 Subunits (E1) (as dimers) E2 Dihydrolypoly transacetlyase core (trimers) a+b

  33. Table 17-1