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Application of Carbohydrate Metabolism

Application of Carbohydrate Metabolism. Review of Allosteric sites. Futile Cycling. Insulin and Glucagon. Amino Sugars. Glucose. Glucose. Glucose. Glucose. J = 0. J = 0. V F > V R. V F < V R. Rate-controlling Step. Rate-controlling Step. Rate-controlling

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Application of Carbohydrate Metabolism

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  1. Application of Carbohydrate Metabolism Review of Allosteric sites Futile Cycling Insulin and Glucagon Amino Sugars

  2. Glucose Glucose Glucose Glucose J = 0 J = 0 VF > VR VF < VR Rate-controlling Step Rate-controlling Step Rate-controlling Step Rate-controlling Step Lactate Lactate Lactate Lactate

  3. [ATP][AMP] K = [ADP]2 Adenylate kinase Rule: the balance of ATP, ADP, and AMP in a cell is controlled by adenylate kinase. Reactions that elevate ADP elevate AMP, a major allosteric regulator. Equation + AMP 2ADP ATP Biological Reality 100 ATP 10 2 ADP AMP Rule: A small change in ATP will have a strongly magnifying effect on ADP or AMP concentrations in the cell

  4. [ATP][AMP] K = 10 100 2 [ADP]2 ATP ADP AMP Examples in Working Muscle 0.1 mM 1 mM 0.02 mM If ATP concentration drops by 10%, adenylate kinase will readjust the levels of ADP and AMP to compensate 100% -10% >400% ATP ADP AMP 0.2 mM 0.9 mM ~0.1 mM

  5. Key ALLOSTERIC Regulatory Points F6P Glucose PFK-1 F6BPtase HK G6Ptase FBP -ATP -AMP G6P G6P -Citrate -F2,6P +AMP +F2,6P PYR PEP OAA F6P PK PC PEPCK PFK-2 FBPase-2 PYR PEP OAA F2,6P -Alanine +Glucagon, cAMP +Acetyl-CoA -F6P +F1,6BP -Citrate +AMP GLYCOLYSIS-GLUCONEOGENESIS -ATP No Allostery

  6. Fructose-2,6-Bisphosphate • A Major Allosteric Regulator • Synthesized by Phosphofructokinase-2 • Destroyed by Fructose-2,6-Bisphosphatase • Powerful Activator of Glycolysis • Powerful Inhibitor of Gluconeogenesis • Not an Intermediate in any Pathway

  7. O3POCH2 OH O 2 1 6 PO3= PO3= CH2OH O3POCH2 OH Fructose-6-P O Fructose-1,6BP CH2OH -D-Fructose-2,6BP

  8. Fructose 2,6 Bisphosphate STIMULATES GLYCOLYSIS INHIBITS GLUCONEOGENESIS

  9. (-)Citrate Fructose-2,6-bisPO4 (F2,6BP) the most important allosteric effector that regulates glycolysis-gluconeogenesis Activates PFK-1 Inhibits F1,6-bisPtase F2,6BP level controlled by rates of synthesis and degradation F6P F2,6BP PFK-2 Both in Same Protein FBPtase-2 F6P F2,6BP (-)F6P (+)AMP (+)Glycerol-3-PO4 PFK-2 FBP-2 (+)F6P Gluconeogenesis Glycolysis

  10. See P. 458 Glucagon Epinephrine cAMP ATP ADP cAPK PFK2 (a) Kinase PFK2 (b) P P FBPase2 (a) FBPase2 (b) Phosphatase ATP ADP cAPK Glucagon Epinephrine Hormonal Control of F2,6BP Liver Inhibits glycolysis Stimulates gluconeogenesis cAMP IN LIVER: cAMP activates the phosphatase that destroys F2,6BP and inhibits the kinase that makes F2,6BP. The combined effect is to stimulate gluconeogenesis in liver.

  11. PO4 ATP H20 ADP FUTILE CYCLING F6P F1,6BP At steady-state, net reaction is: ATP + H2O ADP + PO4 TAKE HOME: To prevent futile cycling, rates of synthesis and degradation in an ATP-dependent step must not be the same.

  12. See Page 686 in Textbook INSULIN VS GLUCAGON Insulin: Stimulates Glycolysis, Glycogen Synthesis Insulin is designed to remove blood glucose and allow cells to metabolized the glucose or make glycogen Insulin inhibits gluconeogenesis Glucagon: Promotes Gluconeogenesis, Glycogen Breakdown Glucagon is designed to raise blood glucose and assist liver in controlling blood glucose levels Elevates cAMP in liver and stimulates protein phosphorylation Glycogen Synthase Targets: PEPCK PK FBPtase-2 Glycogen Phosphorylase

  13. Amino Sugars • Synthesized from D-fructose • Amine group donated by glutamine • Acetylated • Found in GAGS, proteoglycans and glycoproteins • Examples are N-acetylglucosamine, N-acetylgalactosamine, N-acetylneuraminic acid (Sialic acid)

  14. 2nd C CHO CHO CH2OH COO- C-N C=O C-NH3 H3N- H- H- C-H HO-C HO-C HO-C CH2 C-OH C-OH C-OH CH2 C-OH C-OH C-OH C-NH2 CH2OP CH2OP CH2OP O F-6-P L-Glutamine -C-CH3 O AMINO SUGARS + D-Glucosamine Amidotransferase Acetyl-CoA N-Acetyl-D-glucosamine

  15. Assembly of polypeptide chain with Asn-X-Ser/Thr on ribosomes Final tailoring of oligosaccharide chains in Golgi Finished product for secretion or intracellular targeting 3-Stages of Glycoprotein Synthesis Assembly of oligosaccharide chains on Dolichol

  16. Energy in Glucose (Aerobic) Glucose F1,6BP: -2 ATP F1,6BP 2 Pyr: 4 ATP 2 NADH 6 ATP Mitochondria 2Pyr 2Acetyl-CoA: 2NADH = 6 ATP 2Acetyl-CoA 4CO2 24 ATP 38 ATP C6H12O6 + 6O2 6CO2 + 6H2O Go’= -2,850 kJ/mol Conserved = 38 ATP x 30.5 kJ/ATP = 1,159 kJ Efficiency = 40.7%

  17. Energy in Succinate Succinate Fumarate: 1 FADH2 = 2 ATP Fumarate Malate: 0 Malate OAA: 1 NADH = 3 ATP OAA 4CO2:2 cycles = 24 ATP Total = 29 ATP

  18. C4H6O4 3½ O2 4CO2 + 3H2O + CHO COOH H-C-OH CH2 HO-C-H C6H12O6 + 6O2 6CO2 + 6H2O CH2 H-C-OH COOH H-C-OH CH2OH Succinate Glucose

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