2. Metabolism Dr. Henriëtte Schlüpmann Dr. Fons Cremers

3. Chapters 1-8

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!

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 !

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

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

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

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

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