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Application of Carbohydrate Metabolism

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Presentation on theme: "Application of Carbohydrate Metabolism"— Presentation transcript:

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

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

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. Equation K = [ATP][AMP] [ADP]2 2ADP ATP + AMP 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 ATP Examples in Working Muscle ADP K = [ATP][AMP] [ADP]2 ADP 100
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
GLYCOLYSIS-GLUCONEOGENESIS Glucose G6P HK G6Ptase -Citrate F6P FBP PFK-1 F6BPtase -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-2 FBPase-2 -Citrate +AMP -F6P -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 O O O3POCH2 OH Fructose-6-P Fructose-1,6BP PO3= CH2OH 6 2 OH CH2OH
-D-Fructose-2,6BP 1

8 Fructose 2,6 Bisphosphate

9 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 (-)Citrate (-)F6P (+)AMP (+)Glycerol-3-PO4 PFK-2 FBP-2 (+)F6P Glycolysis Gluconeogenesis

10 Hormonal Control of F2,6BP
See P. 458 Hormonal Control of F2,6BP Glucagon Epinephrine Liver cAPK cAMP PFK2 (a) PFK2 (b) FBPase2 (b) FBPase2 (a) ATP ADP P cAPK Kinase Phosphatase 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.

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 INSULIN VS GLUCAGON See Page 686 in Textbook
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 Targets: PEPCK Glycogen Synthase FBPtase-2 PK 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 Amidotransferase AMINO SUGARS 2nd C CH2OH C=O HO-C CH2OP C-OH F-6-P
COO- C-H CH2 C-NH2 L-Glutamine H3N- O CHO C-NH3 HO-C CH2OP C-OH H- + D-Glucosamine CHO C-N HO-C CH2OP C-OH H- Amidotransferase -C-CH3 O Acetyl-CoA N-Acetyl-D-glucosamine

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)
Glucose F1,6BP: ATP F1,6BP 2 Pyr: ATP 2 NADH ATP Mitochondria 2Pyr 2Acetyl-CoA: 2NADH = 6 ATP 2Acetyl-CoA 4CO ATP 38 ATP C6H12O O2 6CO H2O 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 Succinate C4H6O4 3½ O2 4CO2 + 3H2O + Glucose C6H12O6 + 6O2 6CO2 + 6H2O
COOH CH2 + 3½ O2 4CO H2O C4H6O4 Glucose CHO CH2OH HO-C-H H-C-OH C6H12O O2 6CO H2O

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