1. 29 29-1 OrganicChemistry William H. Brown & Christopher S. Foote

2. 29 29-2 The Organic Chemistry of Metabolism Chapter 29

3. 29 29-3 Introduction  We have now studied the typical reactions of the major classes of organic compounds, and the structure and reactions of carbohydrates and lipids  Now let us apply this background to the study of the organic chemistry of metabolism  We study two key metabolic pathways  -oxidation of fatty acids glycolysis

4. 29 29-4 Five Key Participants  Five of the compounds participating in these and a great many other metabolic pathways: ATPADPAMPATP, ADP, and AMP are universal carriers of phosphate groups NAD + /NADHFAD/FADH 2NAD + /NADH and FAD/FADH 2 are coenzymes involved in the oxidation/reduction of metabolic intermediates Coenzyme:  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

5. 29 29-5 Adenosine Triphosphate  ATP is the most important compound involved in the transfer of phosphate groups

6. 29 29-6 Adenosine Triphosphate hydrolysis of the terminal phosphate of ATP gives ADP and phosphate in glycolysis, the phosphate acceptors are -OH groups of glucose and fructose

7. 29 29-7 Nicotinamide adenine dinucleotide a biological oxidizing agent

8. 29 29-8 NAD + /NADH  NAD + is a two-electron oxidizing agent, and is reduced to NADH

9. 29 29-9 NAD + /NADH NAD + is involved in a variety of enzyme-catalyzed oxidation/reduction reactions; we deal with two of these in this chapter

10. 29 29-10 NAD + /NADH

11. 29 29-11 FAD/FADH 2

12. 29 29-12 FAD/FADH 2  FAD participates in several types of enzyme- catalyzed oxidation/reduction reactions our concern is its participation in the oxidation of a C- C bond in a fatty acid hydrocarbon chain to a C=C bond as shown in these balanced half-reactions

13. 29 29-13 FAD oxidation of C-C

14. 29 29-14 Fatty Acids and Energy  Fatty acids in triglycerides are the principle storage form of energy for most organisms carbon chains are in a highly reduced form the energy yield per gram of fatty acid oxidized is greater than that per gram of carbohydrate

15. 29 29-15 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:   -Oxidation: a series of four enzyme-catalyzed reactions that cleaves carbon atoms two at a time, from the carboxyl end of a fatty acids

16. 29 29-16 Activation of Fatty Acids activation begins in the cytoplasm with formation of a thioester between the carboxyl group of the fatty acid and the sulfhydryl group of coenzyme A formation of the acyl-CoA derivative is coupled with the hydrolysis of ATP to AMP and pyrophosphate

17. 29 29-17  -Oxidation Reaction 1:Reaction 1: stereospecific oxidation of a carbon- carbon single bond  to the carbonyl group Reaction 2:Reaction 2: regiospecific and stereospecific hydration of the carbon-carbon double bond; only the R- enantiomer is formed

18. 29 29-18  -Oxidation Reaction 3:Reaction 3: oxidation of the  -hydroxyl group Reaction 4:Reaction 4: cleavage of the carbon chain by a reverse Claisen condensation

19. 29 29-19  -Oxidation mechanism of the reverse Claisen condensation

20. 29 29-20  -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

21. 29 29-21 Glycolysis  Glycolysis:  Glycolysis: from the Greek, glyko, sweet, and lysis, splitting a series of 10 enzyme-catalyzed reactions by which glucose is oxidized to two molecules of pyruvate

22. 29 29-22 Glycolysis - Rexn 1 phosphorylation of  -D-glucose

23. 29 29-23 Glycolysis - Rexn 2 isomerization of glucose 6-phosphate to fructose 6- phosphate

24. 29 29-24 Glycolysis - Rexn 2 this isomerization is most easily seen by considering the open-chain forms of each monosaccharide

25. 29 29-25 Glycolysis - Rexn 3 phosphorylation of fructose 6-phosphate

26. 29 29-26 Glycolysis - Rexn 4 cleavage of fructose 6-phosphate to two triose phosphates

27. 29 29-27 Glycolysis - Rexn 4 reaction 4 is a reverse aldol reaction a key intermediate is an imine formed by the C=O group of fructose 1,6-bisphosphate and an -NH 2 group of the enzyme catalyzing this reaction

28. 29 29-28 Glycolysis - Rexn 4 reverse aldol reaction gives two three-carbon fragments, one as an imine

29. 29 29-29 Glycolysis - Rexn 4 hydrolysis of the imine gives dihydroxyacetone phosphate and regenerates the -NH 2 group of the enzyme

30. 29 29-30 Glycolysis - Rexn 5 isomerization of triose phosphates

31. 29 29-31 Glycolysis - Rexn 6 oxidation of the -CHO group of glyceraldehyde 3- phosphate the -CHO group is oxidized to a carboxyl group which is in turn converted to a carboxylic-phosphoric mixed anhydride the oxidizing agent is NAD +, which is reduced to NADH

32. 29 29-32 Glycolysis - Rexn 6 We divide this reaction into three stages stage 1: formation of a thiohemiacetal stage 2: oxidation of the thiohemiacetal by NAD +

33. 29 29-33 Glycolysis - Rexn 6 stage 3: conversion of the thioester to a mixed anhydride

34. 29 29-34 Glycolysis - Rexn 7 transfer of a phosphate group from 1,3- bisphosphoglycerate to ADP

35. 29 29-35 Glycolysis - Rexn 8 isomerization of 3-phosphoglycerate to 2- phosphoglycerate

36. 29 29-36 Glycolysis - Rexn 9  dehydration of 2-phosphoglycerate

37. 29 29-37 Glycolysis - Rexn 10 phosphate transfer to ADP

38. 29 29-38 Glycolysis Summing these 10 reactions gives the net equation for glycolysis

39. 29 29-39 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

40. 29 29-40 Lactate Fermentation in vertebrates under anaerobic conditions, the most important pathway for the regeneration of NAD + is reduction of pyruvate to lactate

41. 29 29-41 Pyruvate to Lactate while lactate fermentation does allow glycolysis to continue, it increases the concentration of lactate and also of H + in muscle tissue, as seen in this balanced half-reaction when blood lactate reaches about 0.4 mg/100 mL, muscle tissue becomes almost completely exhausted

42. 29 29-42 Pyruvate to Ethanol  Yeasts and several other organisms regenerate NAD + by this two step pathway decarboxylation of pyruvate to acetaldehyde reduction of acetaldehyde to ethanol

43. 29 29-43 Pyruvate to Acetyl-CoA  Under aerobic conditions pyruvate undergoes oxidative decarboxylation the carboxylate group is converted to CO 2 the remaining two carbons are converted to the acetyl group of acetyl-CoA

44. 29 29-44 Pyruvate to Acetyl-CoA  Oxidative decarboxylation of pyruvate to acetyl- CoA is considerably more complex than the previous equation suggests  In addition to NAD + (from the vitamin niacin) and coenzyme A (from the vitamin pantothenic acid), it also requires FAD (from the vitamin riboflavin) pyridoxal phosphate (from the vitamin pyridoxine) lipoic acid

45. 29 29-45 Pyruvate to Acetyl-CoA

46. 29 29-46 Prob 29.21 Describe the type of reaction involved in this biochemical synthesis of  -hydroxybutyrate.

47. 29 29-47 The Organic Chemistry of Metabolism End Chapter 29