Organic Chemistry

1. Organic Chemistry William H. Brown & Christopher S. Foote

2. The Organic Chemistry of Metabolism Chapter 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. Five Key Participants • Five of the compounds participating in these and a great many other metabolic pathways: • ATP, ADP, and AMP are universal carriers of phosphate groups • NAD+/NADHand FAD/FADH2are coenzymes involved in the oxidation/reduction of metabolic intermediates • 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. Adenosine Triphosphate • ATP is the most important compound involved in the transfer of phosphate groups

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. Nicotinamide adenine dinucleotide • a biological oxidizing agent

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

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. NAD+/NADH

11. FAD/FADH2

12. FAD/FADH2 • 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. FAD oxidation of C-C

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. 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 acids

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

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

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

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. 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. Glycolysis - Rexn 1 • phosphorylation of -D-glucose

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

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

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

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

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 -NH2 group of the enzyme catalyzing this reaction

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

29. Glycolysis - Rexn 4 • hydrolysis of the imine gives dihydroxyacetone phosphate and regenerates the -NH2 group of the enzyme

30. Glycolysis - Rexn 5 • isomerization of triose phosphates

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

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

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

36. Glycolysis - Rexn 9 • dehydration of 2-phosphoglycerate

37. Glycolysis - Rexn 10 • phosphate transfer to ADP

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

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

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. 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. Pyruvate to Acetyl-CoA • Under aerobic conditions pyruvate undergoes oxidative decarboxylation • the carboxylate group is converted to CO2 • the remaining two carbons are converted to the acetyl group of acetyl-CoA

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. Pyruvate to Acetyl-CoA

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

47. The Organic Chemistry of Metabolism End Chapter 29