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All reactions/processes that occur in a living organism

Metabolism. All reactions/processes that occur in a living organism. Chemical reactions – Usually catalyzed by enzymes. Protein binding to ligands: P + L ↔ PL transportation – Hemoglobin and Myoglobin bind O 2 Serum Albumin binds fatty acids

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All reactions/processes that occur in a living organism

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  1. Metabolism All reactions/processes that occur in a living organism Chemical reactions – Usually catalyzed by enzymes Protein binding to ligands: P + L ↔ PL transportation – Hemoglobin and Myoglobin bind O2 Serum Albumin binds fatty acids signal transduction – acetylcholine receptor binds acetylcholine Diffusion: nutrients/wastes pass through capillary walls glucose diffuses through glucose transporter across membrane

  2. Metabolism Concepts Thermodynamics applies to metabolism DG = DGº + RT ln Q and DGº = -RT lnK DG = DH - TDS

  3. Living organisms do not violate the 2nd law of thermodynamics In the process of transforming energy, living organisms must increase the entropy of the universe. In order to maintain organization living systems must “ordered” energy from their surroundings (carbohydrates, lipids, and proteins) and return disordered energy (heat) back to their surroundings.

  4. Metabolism Concepts Thermodynamics applies to metabolism DG (but not DGº) must be negative for a process to occur. DG = DGº + RT ln Q and DGº = -RT lnK DG = DH - TDS Free energy to drive reactions in living systems is found in a number of “high energy” molecules. ATP (or other nucleoside triphosphates) Reduced ‘coenzymes’: NADH and FADH2 Thioester coupling e.g. AcetylCoA

  5. Metabolism All reactions/processes that occur in a living organism • Generate Useable Energy • Catabolic/catabolism • Provides cellular energy/ATP 2. Synthesize Molecules/structures Anabolic/anabolism requires energy/ATP

  6. Stages of Catabolism (and to some degree Anabolism) I digestion/hydrolysis Macromolecules → fuels II Oxidation of fuel Glycolysis – glucose b-oxidation – FAs oxidative deamination - Pro makesNADH/FADH2 III ATP production Krebs cycle & Oxidative phosphorylation

  7. E2 E3 E4 E5  C  D  E  F Metabolism All reactions/processes that occur in a living organism PATHWAY E1 A  B metabolic intermediates — a molecule transiently produced in a pathway Metabolite — a molecule produced from some ingested/absorbed molecule

  8. Metabolic Mainstreet Glucose • Generate Useable Energy • (ATP) Catabolic Glycolysis Pyruvate 2. Synthesize Molecular “Parts” Anabolic Bridging Rx. AcetylCoA NAD+/FAD NADH/FADH2 C6 C4 Oxidative Phosphorylation Krebs Cycle ADP O2 C5 C4 ATP

  9. fuel in Oxidative Phosphorylaton Dehydrogenases SH2NADH ATP S NAD+ADP work output NAD+ FAD

  10. ATP + H2O ADP + Pi DG° = -7.3 kcal/mol ATP uses Drive anabolic reactions Active Transport — maintain membrane gradients Energy charge Mechanical Motion (e.g. Muscles) [ATP] + 1/2[ADP] [ATP] + [ADP] + [AMP] G = H - S at equilibrium …… DG = 0, Q = Keq & G= - RT lnKeq G = G+ RT ln Q

  11. ATP use ATP + H2O ADP + Pi DG° = -7.3 kcal/mol Drive anabolic reactions Active Transport — maintain membrane gradients Transition state Activation energy - related to rate ATP + H2O DGº = -7.3 kcal/mol ADP + Pi Mechanical Motion (e.g. Muscles)

  12. ATP + H2O ADP + Pi DG° = -7.3 kcal/mol ADP + H2O AMP + Pi DG° = -7.3 kcal/mol ATP + H2O AMP + PPi DG° = -7.3 kcal/mol PPi + H2O 2PiDG° = -8.0 kcal/mol

  13. Energy Charge (EC) catabolic Energy charge Rate [ATP] + 1/2[ADP] [ATP] + [ADP] + [AMP] anabolic EC 0  1 with AVG  0.85

  14. Cellular ATP concentration is usually far above the equilibrium concentration, making ATP a very potent source of chemical energy.

  15. G = H - S at equilibrium …… DG = 0, Q = Keq & G= - RT lnKeq G = G+ RT ln Q ATP + H2O ADP + Pi DG° = -7.3 kcal/mol Q = [ADP] • [Pi] [ATP] Average [ ]’s in cells [ATP]  8mM [ADP]  [AMP] 1mM Q = 1x10-3 • 8 x 10-3= 1 x 10-3. 8 x 10-3 [Pi]  8mM G = -7.3 + 0.62 ln (0.001) = -11.6 kcal “ An Organism at equilibrium is a dead organism!” “A Cell is always striving to achieve a state of equilibrium, but never succeeding” Enzymatic ATP hydrolysis helps a cell to utilize ATP energy for useful purposes, faster than it will hydrolyze non-enzymatically.

  16. Parallel or Kinetic Coupling Enzyme = “X” Kinase X + Pi X-P DG = + 5.0 ATP  ADP + PiDG = -7.3 X + ATP X-P + ADP DG = -2.3 Series or Thermodynamic CouplingX  Y  Z X  Y DG˚′ = + 4.0 [Y] << [X] Y  Z DG˚′ = -5.0[Y] <<< [Z] X  Z DG˚′ = -1.0[X] < [Z]

  17. Glucose + Pi Glucose-6-P + H2O What is DG°´ for this reaction? Addition of phosphate is the opposite of hydrolysis .... DG°´ = +3.3 kcal/mol Calculate [G-6-P]/[Glucose] at equilibrium ([Pi]  8mM) G= - RT lnKeq [G-6-P]/[Glucose] ~ 3.8 x 10-5

  18. Without coupling[G-6-P]/[Glucose] ~ 3.8 x 10-5 Glucose + ATP  Glucose-6-P + ADP (assume [ATP] = [ADP]) DG°´ = +3.3 – 7.3 = -4.0 G= - RT lnKeq& [G-6-P]/[Glucose] = 634 Coupling with ATP hydrolysis shifted equilibrium > 10 million x not a true equilibrium but rather a steady state

  19. Which molecule is more stable …… a) creatine b) creatine phosphate Which molecule is more stable …… a) 1,3 bisphosphoglycerate b) creatine phosphate What is DG°′ for the reaction ……. 1,3 bisphosphoglycerate + ADP ↔ 3 BPG + ATP a) -22.1 kcal mol-1 b) -7.5 kcal mol-1 c) +7.5 kcal mol-1 d) none of these

  20. Macromolecules digestion/hydrolysis fuels various catabolic pathways NADH/FADH2 Krebs cycle & oxidative phosphorylation ATP

  21. ATP + H2O ADP + Pi DG° = -7.3 kcal/mol ATP uses Drive anabolic reactions Active Transport — maintain membrane gradients Energy charge Mechanical Motion (e.g. Muscles) [ATP] + 1/2[ADP] [ATP] + [ADP] + [AMP] G = H - S at equilibrium …… DG = 0, Q = Keq & G= - RT lnKeq G = G+ RT ln Q

  22. Metabolic Mainstreet Glucose Glycolysis Pyruvate Bridging Rx. AcetylCoA NAD+/FAD NADH/FADH2 C6 C4 OP Krebs Cycle ADP O2 C5 C4 ATP

  23. PATHWAYS: 4 W’s What = Net Reaction Why = Purpose(s) of Pathway Where = Organism/Tissue/Organelle When = Regulation of Pathway

  24. Hydrolysis of ATP is highly favorable under standard conditions • Better charge separation in products • Better solvation of products • More favorable resonance stabilization of products

  25. Actual Gof ATP hydrolysis differs from G’ • The actual free-energy change in a process depends on: • The standard free energy • The actual concentrations of reactants and products • The free-energy change is more favorable if the reactant’s concentration exceeds its equilibrium concentration • True reactant and the product are Mg-ATP and Mg-ADP, respectively • G also Mg++ dependent

  26. Hydrolysis of Thioesters

  27. Reduction Potential • Reduction potential (E) • Affinity for electrons; higher E, higher affinity • Electrons transferred from lower to higher E E’= -(RT/nF)ln (Keq) = G’/nF ∆E’ = E’(e-acceptor) – E’(e-donor) ∆G’ = –nF∆E’ For negative G need positive E E(acceptor) > E(donor)

  28. NAD and NADP are common redox cofactors

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