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

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Presentation on theme: "Application of Carbohydrate Metabolism Futile Cycling Insulin and Glucagon Review of Allosteric sites Amino Sugars."— Presentation transcript:

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

2 Lactate Glucose Lactate Glucose Rate-controlling Step Rate-controlling Step Glucose Rate-controlling Step Lactate Glucose Rate-controlling Step Lactate J = 0 V F > V R V F < V R

3 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. 2ADPATP + AMP Equation Biological Reality ADP ATP AMP Rule:A small change in ATP will have a strongly magnifying effect on ADP or AMP concentrations in the cell K = [ATP][AMP] [ADP] 2

4 Examples in Working Muscle 1 mM0.1 mM0.02 mM ADP ATP AMP If ATP concentration drops by 10%, adenylate kinase will readjust the levels of ADP and AMP to compensate ADP ATP -10% AMP 0.2 mM0.9 mM~0.1 mM 100%>400% K = [ATP][AMP] [ADP] 2

5 Key ALLOSTERIC Regulatory Points GLYCOLYSIS-GLUCONEOGENESIS -Citrate F6P FBP PFK-1F6BPtase -ATP +AMP +F2,6P -AMP -F2,6P PEP PYR PK -Alanine +F1,6BP PYR OAA PC +Acetyl-CoA OAA PEP PEPCK +Glucagon, cAMP F6P F2,6P PFK-2FBPase-2 -Citrate +AMP -F6P Glucose G6P HKG6Ptase G6P -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 Fructose-6-P Fructose-1,6BP O OH O 3 POCH 2 CH 2 OH O OH CH 2 OH O 3 POCH 2  - D -Fructose-2,6BP PO 3 = 2 1 6

8 Fructose 2,6 Bisphosphate STIMULATES GLYCOLYSIS INHIBITS GLUCONEOGENESIS

9 the most important allosteric effector that regulates glycolysis-gluconeogenesis Fructose-2,6-bisPO 4 (F2,6BP) Activates PFK-1 Inhibits F1,6-bisPtase F2,6BP level controlled by rates of synthesis and degradation F6PF2,6BP PFK-2 F2,6BP F6P FBPtase-2 Both in Same Protein PFK-2FBP-2 (-)Citrate (-)F6P (+)AMP (+)F6P (+)Glycerol-3-PO 4 Glycolysis Gluconeogenesis

10 Hormonal Control of F2,6BP Liver PFK2 (a) PFK2 (b) FBPase2 (b) FBPase2 (a) ATP ADP P P cAPK Kinase Phosphatase See P. 458 Inhibits glycolysis Stimulates gluconeogenesis cAPK cAMP Glucagon Epinephrine Glucagon Epinephrine Glucagon Epinephrine Glucagon Epinephrine 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. 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 F6P F1,6BP ATP ADP FUTILE CYCLING At steady-state, net reaction is: PO 4 H20H20 ATP + H 2 OADP + PO 4 TAKE HOME: To prevent futile cycling, rates of synthesis and degradation in an ATP-dependent step must not be the same.

12 Insulin: Stimulates Glycolysis, Glycogen Synthesis Glucagon: Promotes Gluconeogenesis, Glycogen Breakdown Insulin is designed to remove blood glucose and allow cells to metabolized the glucose or make glycogen Glucagon is designed to raise blood glucose and assist liver in controlling blood glucose levels Elevates cAMP in liver and stimulates protein phosphorylation See Page 686 in Textbook Insulin inhibits gluconeogenesis INSULIN VS GLUCAGON Targets: PEPCK FBPtase-2 PK Glycogen Synthase 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 COO - C-H CH 2 C-NH 2 L-Glutamine H 3 N- CH 2 O + AMINO SUGARS CH 2 OH C=O HO-C CH 2 OP C-OH F-6-P CHO C-NH 3 HO-C CH 2 OP C-OH H- 2 nd C D-Glucosamine CHO C-N HO-C CH 2 OP C-OH H- -C-CH 3 O Acetyl-CoA N-Acetyl-D-glucosamine Amidotransferase

15 3-Stages of Glycoprotein Synthesis Assembly of oligosaccharide chains on Dolichol 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

16 Energy in Glucose (Aerobic) GlucoseF1,6BP:-2 ATP F1,6BP2 Pyr:4 ATP 2 NADH6 ATP 2Pyr 2Acetyl-CoA: 2NADH = 6 ATP 2Acetyl-CoA 4CO 2 24 ATP 38 ATP Mitochondria C 6 H 12 O 6 + 6O 2 6CO 2 + 6H 2 O  G o’ = -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 FADH 2 = 2 ATP FumarateMalate:0 MalateOAA:1 NADH = 3 ATP OAA4CO 2 :2 cycles = 24 ATP Total= 29 ATP

18 COOH CH 2 COOH CH 2 + 3½ O 2 4CO 2 + 3H 2 O C4H6O4C4H6O4 C 6 H 12 O 6 + 6O 2 6CO 2 + 6H 2 O CHO CH 2 O H HO-C-H H-C-OH Succinate Glucose


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