1. The Chemistry of Metabolism
Chapter 19
The Chemistry of Metabolism

2. Introduction
We have now studied the typical reactions of the major classes of organic compounds and the structure and reactions of carbohydrates, nucleic acids, and lipids
We now apply this background to the study of the organic chemistry of metabolism
glycolysis
-oxidation of fatty acids
the citric acid cycle

3. Metabolism
The process by which organisms acquire and use energy to carry out various functions.
Organisms are not at equilibrium; they couple reactions that release energy with reactions that require energy.
Plants and certain bacteria obtain free energy from the sun; other organisms must obtain energy by oxidizing organic compounds.

4. Metabolism
Metabolic reaction pathways are generally divided into two categories
Catabolism: pathways that are involved in breaking down nutrients into small organic molecules, these usually release energy
Anabolism: pathways that that are involved in synthesis of larger complex molecules, these usually require energy
Catabolism and anabolism are not simply the reverse of each other, they are separate sets of pathways.

5. Overview of Metabolism

6. Digestion
Enzymes break down complex macromolecules:

7. Digestion
Breakdown of smaller molecules:

8. Anabolism
Biosynthesis of macromolecules:

9. Anabolism
Biosynthesis of macromolecules:

10. Five Key Participants
Five compounds participating in these and a great many other metabolic pathways:
ATP, ADP, and AMP are universal carriers of phosphate groups
NAD+/NADH and FAD/FADH2 are coenzymes involved in oxidation/reduction of metabolic intermediates; they are universal transporters of electrons
Coenzyme: a low-molecular-weight, nonprotein molecule or ion that binds reversibly to an enzyme, functions as a second substrate, and is regenerated by further reaction

11. Adenosine Triphosphate (ATP)
ATP is the most important of the compounds involved in the transfer of phosphate groups

12. Adenosine Triphosphate (ATP)
Hydrolysis of the terminal phosphate of ATP gives ADP and phosphate
in glycolysis, for example, the phosphate acceptors are -OH groups of glucose and fructose

13. NAD+/NADH
Nicotinamide adenine dinucleotide (NAD+) is a biological oxidizing agent

14. NAD+/NADH
when NAD+ acids acts as a biological oxidizing agent, it is reduced to NADH
when NADH acts as a biological reducing agent, it is oxidized to NAD+

15. NAD+/NADH
its redox reactions involve transfer of a hydride ion, H:-

16. FAD/FADH2
Flavin adenine dinucleotide (FAD) is also a biological oxidizing agent

17. FAD/FADH2
when FAD functions as an oxidizing agent, it is reduced to FADH2

18. Coenzyme A
Coenzyme A (Co-A) is a carrier of acetyl groups as acetyl coenzyme A (acetyl-CoA)
the acetyl group is bound to the -SH group as a thioester

19. Glycolysis
Breakdown of glucose – synthesis of pyruvate for citric acid cycle

20. Glycolysis
Reaction 1: Phosphorylation of Glucose

21. Glycolysis
Reaction 2: Isomerization

22. Glycolysis
Reaction 3: Phosphorylation

23. Glycolysis
Reaction 4: Cleavage

24. Glycolysis
Reaction 5: Isomerization

25. Glycolysis
Reaction 6: Oxidation (exothermic)

26. Glycolysis
Reaction 7: Formation of ATP

27. Glycolysis
Reaction 8: Formation of 2-Phosphoglycerate

28. Glycolysis
Reaction 9: Formation of Phosphoenolpyruvate (PEP)

29. Glycolysis
Reaction 10: Formation of ATP

30. Glycolysis Reaction 10: Formation of ATP
Pyruvate reacts with CoASH to make Acetyl-CoA and enters Citric Acid Cycle

31. Fates of Pyruvate
Pyruvate does not accumulate in cells, but rather undergoes one of three enzyme-catalyzed reactions, depending of the type of cell and its state of oxygenation
reduction to lactate
reduction to ethanol
oxidation and decarboxylation to acetyl-CoA
A key to understanding the biochemical logic behind two of these fates is to recognize that glycolysis needs a continuing supply of NAD+
if no oxygen is present to reoxidize NADH to NAD+, then another way must be found to do it

32. Pyruvate to Lactate
in vertebrates under anaerobic conditions, the most important pathway for the regeneration of NAD+ is reduction of pyruvate to lactate

33. Pyruvate to Lactate
while lactate fermentation does allow glycolysis to continue, it increases the concentration of lactate and also of H+ in muscle tissue
when blood lactate reaches about 0.4 mg/100 mL, muscle tissue becomes almost completely exhausted

34. Reduction to Ethanol
yeasts and several other organisms regenerate NAD+ by this two-step pathway, known as alcoholic fermentation

35. Oxidation to Acetyl-CoA
this conversion requires both thiamine pyrophosphate and lipoic acid

36. The Citric Acid Cycle

37. The Citric Acid Cycle
Reaction 1: Formation of Citrate

38. The Citric Acid Cycle
Reaction 2: Isomerization to Isocitrate

39. The Citric Acid Cycle
Reaction 3: First Oxidative Decarboxylation

40. The Citric Acid Cycle
Reaction 4: Second Oxidative Decarboxylation

41. The Citric Acid Cycle
Reaction 5: Hydrolysis of Succinyl-CoA

42. The Citric Acid Cycle
Reaction 6: Dehydrogenation of Succinate

43. The Citric Acid Cycle
Reaction 7: Hydration of Fumarate

44. The Citric Acid Cycle
Reaction 8: Dehydrogenation forms Oxaloacetate

45. Oxidative Phosphorylation
NADH and FADH2 produced in Citric Acid Cycle undergo oxidative phosphorylation.
Oxygen is reduced to water with the formation of ATP from ADP.
One mole of glucose is metabolized to form a net of 36 moles of ATP.

46. Citric Acid Cycle
as seen from the balanced equation for the cycle, it is truly catalytic
the intermediates in the cycle are neither synthesized nor destroyed in the net reaction

47. Oxidation of Fatty Acids
There are two major stages in the oxidation of fatty acids
activation of the free fatty acid in the cytoplasm and its transport across the inner mitochondrial membrane
-oxidation
-Oxidation: a series of four enzyme-catalyzed reactions that cleaves carbon atoms two at a time from the carboxyl end of a fatty acid

48. Activation of Fatty Acids
begins in the cytoplasm with formation of a thioester
formation of the thioester is coupled with the hydrolysis of ATP to AMP and pyrophosphate

49. Activation of Fatty Acids
activation of a fatty acid involves ATP

50. Activation of Fatty Acids
and then reaction with coenzyme A

51. -Oxidation
Reaction 1: oxidation of a carbon-carbon single bond to a carbon-carbon double bond

52. -Oxidation
Reaction 2: hydration of the carbon-carbon double bond; only the R enantiomer is formed

53. -Oxidation
Reaction 3: oxidation of the -hydroxyl group to a carbonyl group

54. -Oxidation
Reaction 4: cleavage of the carbon chain by a reverse Claisen condensation

55. -Oxidation Spiral

56. -Oxidation
this series of reactions is then repeated on the shortened fatty acyl chain and continues until the entire fatty acid chain is degraded to acetyl-CoA