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  • 1.  
  • 2. Metabolism Dr. Henriëtte Schlüpmann Dr. Fons Cremers
  • 3. Chapters 1-8
  • 4.  
  • 5.  
  • 6.  
  • 7. Start from well known metabolites
  • 8. Beware chemical formalism is a language!
  • 9. TATA-Box binding protein is similar in diverse organisms
  • 10. The tree of life
  • 11. Time line for biochemical evolution
  • 12. Energy metabolism Chapters 15 -20
  • 13. Energy storage Chapters 21-23
  • 14. Amino Acids Chapter 24
  • 15. Nucleotides Chapter 25
  • 16. Lipids and steroids Chapter 26
  • 17. Integration of metabolism Chapter 27 Your Presentations!
  • 18. Content
    • Metabolism , Dr. Henriëtte Schlüpmann
    • Chapters 11,12, 15,16,17,18,20,21,22,23,24,25,26,27
    • Guest Lectures:
    • Dr. Margriet Hendriks (ABC Metabolomics UMC)
    • Vr 15 Oct 1500 Ruppert 040
    • Dr. Tita Ritsema (AMT Amsterdam)
    • Vr 22 Oct 1500 WENT Groen
    • Presentations:
    • Vr 5 nov 2010 BBL-001 and BBL-023
  • 19. Biochemistry Sixth Edition Chapter 15: Metabolism: Basic Concepts and Design Copyright © 2007 by W. H. Freeman and Company Berg • Tymoczko • Stryer
  • 20. The ruby-throated hummingbird can store enough fuel to fly 500 miles across the Gulf of Mexico A prodigious feat of metabolism,
  • 21. How does a cell extract energy and reducing power from its environment? How does a cell synthesize building blocks and macro-molecules?
  • 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
  • 23. Fuel (Carbohydrates, fats) CO 2 + H 2 O + energy Catabolism Energy + simple precursors complex molecules Anabolism
  • 24. Metabolism is composed of many coupled interconnecting reactions
  • 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
  • 26. ATP is the universal currency of free energy in biological systems
  • 27. Adenine Ribose Phosphate
  • 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 !
  • 29.
    • ATP hydrolysis drives metabolism by shifting the equilibrium of coupled reactions
    • A B  G 0 ’= +16.7 kJ mol -1 = -RT ln (K’ eq )
    • K’ eq = [B] eq /[A] eq = 10 -  G0’/5.69 = 1.15 x 10 -3
        • A + ATP + H 2 O B + ADP + Pi  G 0 ’= -13.8 kJ mol -1
    • K’ eq = [B] eq x [ADP] eq [Pi] eq = 10 – 13.8/5.69 = 2.67 x 10 2
    • [A] eq [ATP] eq
    [B] eq [A] eq = K’ eq [ATP] eq [ADP] eq [Pi] eq
  • 30.
    • ATP hydrolysis drives metabolism by shifting the equilibrium of coupled reactions
    • A B  G 0 ’= +16.7 kJ mol -1 = -RT ln (K’ eq )
    • K’ eq = [B] eq /[A] eq = 10 -  G0’/5.69 = 1.15 x 10 -3
        • A + ATP + H 2 O B + ADP + Pi  G 0 ’= -13.8 kJ mol -1
    • K’ eq = [B] eq x [ADP] eq [Pi] eq = 10 – 13.8/5.69 = 2.67 x 10 2
    • [A] eq [ATP] eq
    [B] eq [A] eq = K’ eq [ATP] eq [ADP] eq [Pi] eq
  • 31. Myosin conformations
  • 32. Calcium channel comformations
  • 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
  • 34.  
  • 35. Phosphoryl transfer potential is an important form of cellular energy transformation
  • 36. Sources of ATP during exercise: there is very little ATP but it does get recycled at a tremendous rate
  • 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
  • 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.
  • 39. Fats are a more efficient fuel source than the more oxidized carbohydrates Prominent Fuels
  • 40. Compounds with high phosphoryl transfer potential can couple carbon oxidation to ATP synthesis
  • 41. Oxidation with NAD first generates an acyl phosphate: 1,3 bisphosphoglycerate with higher phosphoryl transfer potential than ATP
  • 42. Oxidation with NAD first generates an acyl phosphate: 1,3 bisphosphoglycerate with higher phosphoryl transfer potential than ATP
  • 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
  • 44. Energy from foodstuffs is extracted in three stages
  • 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
  • 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
  • 47. Structure of oxidised forms of nicotineamide adenine dinucleotide (NAD + ) R=H, and NADP + R=PO 3 2-
  • 48. FAD coupled reductions convert single to double bond carbon bonds
  • 49. Flavin mononucleotide (FMN) AMP
  • 50.  
  • 51. Activated carrier of e- for reductive biosynthesis NADPH
  • 52. Activated carrier of two-carbon fragments Coenzyme A
  • 53. Acyl groups are linked to CoA by thioester bonds
  • 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
  • 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
  • 56. ADP a toutes les sauces: Co-enzymes may have evolved from early RNA catalysts
  • 57.  
  • 58.  
  • 59.  
  • 60.
    • Key reactions are reiterated throughout metabolism
        • Oxidation-reduction
        • Ligation
        • Isomerization
        • Group-transfer
        • Hydrolytic
        • Addition/removal of functional groups by lyases
    An effective way to learn is to look for commonalities in the diverse metabolisc pathways
  • 61.  
  • 62. Oxidation-reduction reactions
  • 63. Ligation reactions
  • 64. Isomerization reactions
  • 65. Group-transfer reactions
  • 66. Hydrolytic reactions
  • 67. Reactions in which functional groups are added to double bonds
  • 68.  
  • 69.
    • Metabolic processes are regulated:
      • Amount of enzyme
      • Catalytic activity
      • Substrate accessibility
  • 70.
    • Enzymes amounts result from synthesis and degradation rates:
            • Transcription,
            • translation and
            • modifications that affect stability
  • 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
  • 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 =
  • 73. Controlling accessibility of substrates Enzymes of specific pathways are in differing sub-cellular compartments Control of substrate flux