1. © 2011 Pearson Education, Inc. 1 Chapter 26 The Organic Chemistry of the Metabolic Pathways Organic Chemistry 6 th Edition Paula Yurkanis Bruice

2. © 2011 Pearson Education, Inc. 2 Metabolism is the set of reactions living organisms carry out to obtain energy and to synthesize complex molecules catabolism: complex molecules simple molecules + energy anabolism: simple molecules + energy complex molecules Metabolism is the combination of catabolism and anabolism

3. © 2011 Pearson Education, Inc. 3 The Four Stages of Catabolism

4. © 2011 Pearson Education, Inc. 4 Compounds that can enter the citric acid cycle are citric acid cycle intermediates, acetyl-coA, and pyruvate. Pyruvate enters the cycle by being converted to acetyl-CoA. Acetyl-CoA is the only non–citric acid cycle intermediate that can enter the citric acid cycle by being converted to citrate.

5. © 2011 Pearson Education, Inc. 5 Metabolic Energy Is Measured in Terms of Adenosine Triphosphate (ATP) ATP is the universal carrier of chemical energy The energy released from hydrolysis of ATP converts endergonic reactions into exergonic reactions

6. © 2011 Pearson Education, Inc. 6 A phosphoanhydride bond is broken in this reaction Thermodynamics of glucose-6-phosphate formation:

7. © 2011 Pearson Education, Inc. 7 Mechanism for a phosphoryl transfer reaction:

8. © 2011 Pearson Education, Inc. 8 Without ATP, phosphorylation cannot occur:

9. © 2011 Pearson Education, Inc. 9 Three Mechanisms for Phosphoryl Transfer Reactions Each of the three phosphorus atoms of ATP can undergo nucleophilic attack. Each mechanism places a different phosphoryl group on the nucleophile.

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13. © 2011 Pearson Education, Inc. 13 The pyrophosphate product is further hydrolyzed to ensure irreversibility of the reactions:

14. © 2011 Pearson Education, Inc. 14 The “High-Energy” Character of Phosphoanhydride Bonds The hydrolysis of a phosphoanhydride bond is highly exergonic

15. © 2011 Pearson Education, Inc. 15 Three Factors Contribute to the Greater Stability of ADP and Phosphate Compared to ATP 1.Greater electrostatic repulsion in ATP 2.More solvation stabilization in the products 3.Greater electron delocalization in the products

16. © 2011 Pearson Education, Inc. 16 ATP reacts slowly in the absence of enzymes because the negative charges on ATP decrease leaving ability In an enzyme active site, positive centers decrease the overall negative charge

17. © 2011 Pearson Education, Inc. 17 The Catabolism of Fats

18. © 2011 Pearson Education, Inc. 18 A kinase is an enzyme that puts a phosphoryl group on its substrate. A dehydrogenase is an enzyme that oxidizes its substrate. Dihydroxyacetone phosphate enters the glycolytic pathway and is broken down further.

19. © 2011 Pearson Education, Inc. 19 Mechanism for the conversion of glycerol-3-phosphate to dihydroxyacetone phosphate:

20. © 2011 Pearson Education, Inc. 20 A fatty acid has to be activated before it can be metabolized:

21. © 2011 Pearson Education, Inc. 21 The fatty acyl-CoA is converted to acetyl-CoA via  -oxidation: 1. acyl-CoA dehydrogenase 2. enoyl-CoA hydratase 3. 3-L-hydroxyacyl-CoA dehydrogenase  -ketoacyl-CoA thiolase

22. © 2011 Pearson Education, Inc. 22 Reaction mechanisms Conjugate addition of water: A retro-Claisen condensation:

23. © 2011 Pearson Education, Inc. 23 The Catabolism of Carbohydrates In the first stage of carbohydrate catabolism, polysaccharides are enzymatically hydrolyzed to glucose molecules:

24. © 2011 Pearson Education, Inc. 24 Glucose is converted to two molecules of pyruvate by the 10-step process known as the glycolytic pathway: 1. Glucose is converted to glucose-6-phosphate (Section 26.1) 2. Glucose-6-phosphate isomerizes to fructose-6-phosphate (Section 24.9) 3. ATP puts a second phosphoryl group on fructose-6-phosphate to yield fructose-1,6-diphosphate 4. The reverse of an aldol reaction (Section 24.9) 5.

25. © 2011 Pearson Education, Inc. 25 Mechanism of step 5: Compare this mechanism with the enediol rearrangement shown in Section 22.5

26. © 2011 Pearson Education, Inc. 26 6. Glyceraldehyde-3-phosphate is oxidized by NAD + to yield 1,3- diphosphoglycerate (Section 25.1) 7. ATP formation 8. Isomerization

27. © 2011 Pearson Education, Inc. 27 9. Dehydration 10. ATP formation

28. © 2011 Pearson Education, Inc. 28 Glycolysis

29. © 2011 Pearson Education, Inc. 29 The Fates of Pyruvate Aerobic conditions: Anaerobic conditions:

30. © 2011 Pearson Education, Inc. 30 Yeast converts pyruvate to ethanol:

31. © 2011 Pearson Education, Inc. 31 The Catabolism of Proteins Amino acids are then converted to acetyl-CoA, pyruvate, or citric acid cycle intermediates The first stage of protein catabolism is enzymatic hydrolysis of proteins to amino acids:

32. © 2011 Pearson Education, Inc. 32 An Example of Amino Acid Catabolism

33. © 2011 Pearson Education, Inc. 33 The Citric Acid Cycle The acetyl group of each molecule of acetyl- CoA is formed by the catabolism of fats, carbohydrates, and amino acids

34. © 2011 Pearson Education, Inc. 34 The Citric Acid Cycle Contains Eight Reactions

35. © 2011 Pearson Education, Inc. 35 1. Carbonyl addition and hydrolysis (Sections 18.2 and 17.5) 2. Dehydration and conjugate addition of water (Section 18.18)

36. © 2011 Pearson Education, Inc. 36 3. Oxidation and decarboxylation (Section 19.19) 4. Oxidation and decarboxylation (Section 25.3)

37. © 2011 Pearson Education, Inc. 37 5. Addition–elimination reaction followed by phosphate transfer to GDP 6. FAD oxidizes succinate to fumarate (Section 25.2) 7. Conjugate addition of water to the double bond of fumarate forms (S)-malate (Section 5.20) 8. Oxidation of the (S)-malate by NAD + forms oxaloacetate, returning the cycle to its starting point Reactions 6, 7, and 8 in the citric acid cycle are similar to reactions 1, 2, and 3 in β-oxidation of fatty acids (Section 26.6)

38. © 2011 Pearson Education, Inc. 38 Oxidative Phosphorylation For every acetyl-CoA that enters the citric acid cycle, 11 molecules of ATP are formed from NADH and FADH 2, and one molecule of ATP is formed in the cycle