Basic concepts

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Basic concepts

  1. 2. Metabolism Dr. Henriëtte Schlüpmann Dr. Fons Cremers
  2. 3. Chapters 1-8
  3. 7. Start from well known metabolites
  4. 8. Beware chemical formalism is a language!
  5. 9. TATA-Box binding protein is similar in diverse organisms
  6. 10. The tree of life
  7. 11. Time line for biochemical evolution
  8. 12. Energy metabolism Chapters 15 -20
  9. 13. Energy storage Chapters 21-23
  10. 14. Amino Acids Chapter 24
  11. 15. Nucleotides Chapter 25
  12. 16. Lipids and steroids Chapter 26
  13. 17. Integration of metabolism Chapter 27 Your Presentations!
  14. 18. Content <ul><li>Metabolism , Dr. Henriëtte Schlüpmann </li></ul><ul><li>Chapters 11,12, 15,16,17,18,20,21,22,23,24,25,26,27 </li></ul><ul><li>Guest Lectures: </li></ul><ul><li>Dr. Margriet Hendriks (ABC Metabolomics UMC) </li></ul><ul><li>Vr 15 Oct 1500 Ruppert 040 </li></ul><ul><li>Dr. Tita Ritsema (AMT Amsterdam) </li></ul><ul><li>Vr 22 Oct 1500 WENT Groen </li></ul><ul><li>Presentations: </li></ul><ul><li>Vr 5 nov 2010 BBL-001 and BBL-023 </li></ul>
  15. 19. Biochemistry Sixth Edition Chapter 15: Metabolism: Basic Concepts and Design Copyright © 2007 by W. H. Freeman and Company Berg • Tymoczko • Stryer
  16. 20. The ruby-throated hummingbird can store enough fuel to fly 500 miles across the Gulf of Mexico A prodigious feat of metabolism,
  17. 21. How does a cell extract energy and reducing power from its environment? How does a cell synthesize building blocks and macro-molecules?
  18. 22. The network of chemical reactions has a coherent design containing many common motifs For example, glucose metabolism is conserved from bacteria to humans Catabolism Anabolism
  19. 23. Fuel (Carbohydrates, fats) CO 2 + H 2 O + energy Catabolism Energy + simple precursors complex molecules Anabolism
  20. 24. Metabolism is composed of many coupled interconnecting reactions
  21. 25. Coupled reactions allow thermodynamically unfavorable reactions to proceed as long as the sum of the free energy changes of coupled reactions is negative. A B + C  G 0 ’= +21 kJ mol -1 B D  G 0 ’= -34 kJ mol -1 A C + D  G 0 ’= -13 kJ mol -1
  22. 26. ATP is the universal currency of free energy in biological systems
  23. 27. Adenine Ribose Phosphate
  24. 28. ATP + H 2 O ADP + Pi  G 0 ’= -30.5 kJ mol -1 ATP + H 2 O AMP + PPi  G 0 ’= -45.6 kJ mol -1 ATP hydrolysis is exergonic !
  25. 29. <ul><li>ATP hydrolysis drives metabolism by shifting the equilibrium of coupled reactions </li></ul><ul><li>A B  G 0 ’= +16.7 kJ mol -1 = -RT ln (K’ eq ) </li></ul><ul><li>K’ eq = [B] eq /[A] eq = 10 -  G0’/5.69 = 1.15 x 10 -3 </li></ul><ul><ul><ul><li>A + ATP + H 2 O B + ADP + Pi  G 0 ’= -13.8 kJ mol -1 </li></ul></ul></ul><ul><li>K’ eq = [B] eq x [ADP] eq [Pi] eq = 10 – 13.8/5.69 = 2.67 x 10 2 </li></ul><ul><li> [A] eq [ATP] eq </li></ul>[B] eq [A] eq = K’ eq [ATP] eq [ADP] eq [Pi] eq
  26. 30. <ul><li>ATP hydrolysis drives metabolism by shifting the equilibrium of coupled reactions </li></ul><ul><li>A B  G 0 ’= +16.7 kJ mol -1 = -RT ln (K’ eq ) </li></ul><ul><li>K’ eq = [B] eq /[A] eq = 10 -  G0’/5.69 = 1.15 x 10 -3 </li></ul><ul><ul><ul><li>A + ATP + H 2 O B + ADP + Pi  G 0 ’= -13.8 kJ mol -1 </li></ul></ul></ul><ul><li>K’ eq = [B] eq x [ADP] eq [Pi] eq = 10 – 13.8/5.69 = 2.67 x 10 2 </li></ul><ul><li> [A] eq [ATP] eq </li></ul>[B] eq [A] eq = K’ eq [ATP] eq [ADP] eq [Pi] eq
  27. 31. Myosin conformations
  28. 32. Calcium channel comformations
  29. 33. The high phosphoryl transfer potential of ATP results from structural differences between ATP and its hydrolysis products Resonance stabilization of Pi and ADP Electrostatic repulsion, triphosphate of ATP has 4 negative charges at pH 7 Stabilization due to hydration, ADP and Pi can bind more water than ATP
  30. 35. Phosphoryl transfer potential is an important form of cellular energy transformation
  31. 36. Sources of ATP during exercise: there is very little ATP but it does get recycled at a tremendous rate
  32. 37. Oxidation of carbon fuels is an important source of cellular energy We have 100 g of ATP in our body, during a 2 h run, 60 kg of ATP is utilized
  33. 38. In aerobic organisms, the ultimate e- acceptor in the oxidation of carbon is CO 2 Free energy of oxidation of single-carbon compounds, oxidation occurs one carbon at a time.
  34. 39. Fats are a more efficient fuel source than the more oxidized carbohydrates Prominent Fuels
  35. 40. Compounds with high phosphoryl transfer potential can couple carbon oxidation to ATP synthesis
  36. 41. Oxidation with NAD first generates an acyl phosphate: 1,3 bisphosphoglycerate with higher phosphoryl transfer potential than ATP
  37. 42. Oxidation with NAD first generates an acyl phosphate: 1,3 bisphosphoglycerate with higher phosphoryl transfer potential than ATP
  38. 43. Ion gradients across membranes are an effective means of storing free energy In animals, proton gradients generated from oxidation of carbon fuels account for more than 90% of ATP generated
  39. 44. Energy from foodstuffs is extracted in three stages
  40. 45. Metabolic Pathways contain many recurring motifs Activated Carriers of phosphoryl groups, electrons or 2-carbon units Key reactions reiterated 3-level control: enzyme, activity, substrate access
  41. 46. Activated carriers of e- for fuel oxidation: coenzymes NAD + and FAD + NAD: Oxidation is a dehydrogenation with one hydrogen as hydride H- and a proton in solution
  42. 47. Structure of oxidised forms of nicotineamide adenine dinucleotide (NAD + ) R=H, and NADP + R=PO 3 2-
  43. 48. FAD coupled reductions convert single to double bond carbon bonds
  44. 49. Flavin mononucleotide (FMN) AMP
  45. 51. Activated carrier of e- for reductive biosynthesis NADPH
  46. 52. Activated carrier of two-carbon fragments Coenzyme A
  47. 53. Acyl groups are linked to CoA by thioester bonds
  48. 54. Hydrolysis of thioester is thermodynamically more favorable than that of oxygen ester because e- of the C=O bond cannot form resonnance structures with the C-S bond Consequently, Acetyl CoA has high acetyl-group transfer potential Acetyl CoA + H 2 O Acetate + CoA + H +  G 0 ’= -31.4 kJ mol -1
  49. 55. Use of activated carriers illustrates 2 key aspects of metabolism : 1. Kinetic stability in the face of large thermodynamic driving force for reaction: NADH, NADPH and FADH 2 react slowly with O 2 in absence of catalyst ATP and Acetyl CoA react slowly with H 2 O in absence of catalyst 2. Most interchanges of activated groups are accomplished by a rather small set of carriers (Table 15) = conservation and unifying motifs of biochemistry as well as modular design
  50. 56. ADP a toutes les sauces: Co-enzymes may have evolved from early RNA catalysts
  51. 60. <ul><li>Key reactions are reiterated throughout metabolism </li></ul><ul><ul><ul><li>Oxidation-reduction </li></ul></ul></ul><ul><ul><ul><li>Ligation </li></ul></ul></ul><ul><ul><ul><li>Isomerization </li></ul></ul></ul><ul><ul><ul><li>Group-transfer </li></ul></ul></ul><ul><ul><ul><li>Hydrolytic </li></ul></ul></ul><ul><ul><ul><li>Addition/removal of functional groups by lyases </li></ul></ul></ul>An effective way to learn is to look for commonalities in the diverse metabolisc pathways
  52. 62. Oxidation-reduction reactions
  53. 63. Ligation reactions
  54. 64. Isomerization reactions
  55. 65. Group-transfer reactions
  56. 66. Hydrolytic reactions
  57. 67. Reactions in which functional groups are added to double bonds
  58. 69. <ul><li>Metabolic processes are regulated: </li></ul><ul><ul><li>Amount of enzyme </li></ul></ul><ul><ul><li>Catalytic activity </li></ul></ul><ul><ul><li>Substrate accessibility </li></ul></ul>
  59. 70. <ul><li>Enzymes amounts result from synthesis and degradation rates: </li></ul><ul><ul><ul><ul><ul><li>Transcription, </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>translation and </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>modifications that affect stability </li></ul></ul></ul></ul></ul>
  60. 71. Controlling catalytic activity 1. Reversible allosteric control Eg feed back inhibition and feed forward activation 2. Reversible covalent modification Eg phosphorylation by cAMP Kinase
  61. 72. Controlling catalytic activity 1. Reversible allosteric control Eg feed back inhibition and feed forward activation 2. Reversible covalent modification Eg phosphorylation by cAMP Kinase [ATP] + ½ [ADP] [ATP]+ [ADP]+ [AMP] Energy Charge =
  62. 73. Controlling accessibility of substrates Enzymes of specific pathways are in differing sub-cellular compartments Control of substrate flux

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