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Biochemistry

Biochemistry. Lecture 11. Gluconeogenesis. Gluconeogenesis. -Metabolic Pathways are Irreversible ∆G between the 1st & last metabolite is large & neg.

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Biochemistry

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  1. Biochemistry Lecture 11

  2. Gluconeogenesis

  3. Gluconeogenesis -Metabolic Pathways are Irreversible ∆G between the 1st & last metabolite is large & neg. - If 2 metabolites are interconvertible (metab 1 metab 2), the path from Metab 1  Metab 2 must be different from that of Metab 2  Metab 1 A B Metab1 Metab2 Y X

  4. A. Circumventing Pyruvate Kinase - Conversion of Pyruvate to Phosphoenolpyruvate • Carboxylation of pyruvate to oxaloacetate √ • Transport of oxaloacetate out of mitochondria Oxaloacetate cyto mito Oxaloacetate NADH + H+ NADH + H+ NAD+ NAD+ Malate Malate Inner mito. Memb. 3. PEP Carboxykinase: decarboxylates and adds phosphate

  5. B. Circumventing PFK – dephosphorylation of F1,6BP • Dephosphorylation is not phosphorylation in reverse! • Reverse Phosphorylation of ADP by F1,6 BP to generate F6P (and ATP) would be steeply uphill: F1,6 BP + ADP F6P + ATP ∆G° = +3.4 kcal/mol • Instead, dephosphorylation is carried out: F1,6 BP + H2O F6P + PO4 ∆G° = -3.9 kcal/mol • Reverse Phosphorylation would be mediated by PFK • Dephosphorylation is mediated by F1,6BPase

  6. C. Circumventing Hexokinase – dephosphorylation of G6P • Mediated by G6Pase • G6Pase is present only in liver and kidney • Hence, these are the only tissues that can synthesize and secrete glucose into the blood

  7. The Gluconeogenic Response is Activated Largely by the State of Feeding/Fasting Glycogen Blood Glucose Blood Glucose Glucose Blood Glucose Pyruvate Alanine Acetyl CoA FA’s

  8. The Cory Cycle

  9. Gluconeogenesis & Glycolysis can Occur at the Same Time in Different Organs IN MUSCLE IN LIVER Glucose Glucose B L OO D Gluconeogen. Glycolysis Pyruvate Pyruvate Alanine Alanine Lactate Lactate RED BLOOD CELLS Glucose *** The main substrate here is LACTATE*** Pyruvate Lactate

  10. Regulation of Metabolism

  11. Overview of Energy Metabolism FATS POLYSACCHARIDES PROTEINS Stage I Digestion Fatty Acids, Glucose and Amino Acids Glycerol other sugars Stage II Anaerobic Acetyl CoA ADP ATP CoA Stage III Aerobic TCA cycle O2 e- CO2 Oxidative Phosphorylation

  12. Principles of Regulation The flow of metabolites through the pathways is regulated to maintain homeostasis Sometimes, the levels of required metabolites must be altered very rapidly Need to increase the capacity of glycolysis during the action Need to reduce the capacity of glycolysis after the action Need to increases the capacity of gluconeogenesis after successful action

  13. Rates of a Biochemical Reaction • Rates of a biochemical reaction depend on many factors • Concentration of reactants • Activity of the catalyst • Concentration of the enzyme • Intrinsic activity of the enzyme • Concentrations of effectors • Allosteric regulators • Competing substrates • pH, ionic environment • Temperature

  14. Reactions Far From Equilibrium are Common Points of Regulation

  15. Hexokinase • Isozymes are different enzymes that catalyze the same reaction • They typically share similar sequences • Their regulation is often different

  16. P eg. G6P is structurally similar to glucose, and competes with glucose for active site of hexokinase

  17. PFK Allosteric site AMP F6P ATP Active site

  18. Fructose-2,6-bisphosphate

  19. Two Alternative Fates for Pyruvate • Pyruvate can be a source of new glucose • Store energy as glycogen • Generate NADPH via pentose phosphate pathway • Pyruvate can be a source of acetyl-CoA • Store energy as body fat • Make ATP via citric acid cycle • Acetyl-CoA stimulates glucose synthesis by activating pyruvate carboxylase

  20. Pancreas Adrenal Medulla + Glucagon Epinephrine Muscle Liver Brain Glycogen Glycogen + + + + Glucose (Blood) Glucose Glucose + F6P F2,6BP F6P F2,6BP + + PFK PFK F1,6BP F1,6BP PK PK Pyruvate Pyruvate

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