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Introduction to Organic Chemistry 2 ed William H. Brown

Introduction to Organic Chemistry 2 ed William H. Brown. The Organic Chemistry of Metabolism. Chapter 20. Introduction. We have now studied the typical reactions of the major classes of organic compounds and the structure and reactions of carbohydrates and lipids

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Introduction to Organic Chemistry 2 ed William H. Brown

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  1. Introduction to Organic Chemistry2 edWilliam H. Brown

  2. The Organic Chemistry of Metabolism Chapter 20

  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 • We now apply this background to the study of the organic chemistry of metabolism • b-oxidation of fatty acids • glycolysis

  4. Five Key Participants • Five compounds participating in these and a great many other metabolic pathways are: • ATP, ADP, and AMP are universal carriers of phosphate groups • NAD+/NADH and FAD/FADH2are coenzymes involved in oxidation/reduction of metabolic intermediates • Coenzyme: a low-MW, nonprotein molecule or ion that binds reversibly to an enzyme, functions as a second substrate, and is regenerated by further reaction

  5. Adenoside Triphosphate • ATP is the most important of the compounds 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. NAD+/NADH • Nicotinamide adenine dinucleotide (NAD+) is a biological oxidizing agent

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

  9. NAD+/NADH • we will discuss two types of oxidations involving NAD+

  10. Oxidation by NAD+

  11. FAD/FADH2 • Flavin adenine dinucleotide (FAD) is also a biological oxidizing agent Riboflavin

  12. FAD/FADH2 • we discuss one type of oxidation involving FAD, namely oxidation of the hydrocarbon chain of a fatty acid

  13. Oxidation by FAD

  14. Oxidation by FAD

  15. 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

  16. 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 • b-oxidation • b-Oxidation: a series of four enzyme-catalyzed reactions that cleaves carbon atoms two at a time, from the carboxyl end of a fatty acids

  17. 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

  18. Activation of Fatty Acids • activation involves reaction with ATP

  19. Activation of Fatty Acids • and then reaction with coenzyme A

  20. b-Oxidation • Reaction 1: oxidation of a carbon-carbon single bond to a carbon-carbon double bond

  21. b-Oxidation • Reaction 2: hydration of the carbon-carbon double bond; only the R-enantiomer is formed

  22. b-Oxidation • Reaction 3: oxidation of the b-hydroxyl group to a carbonyl group

  23. b-Oxidation • Reaction 4: cleavage of the carbon chain by a reverse Claisen condensation

  24. b-Oxidation • mechanism of the reverse Claisen condensation

  25. b-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

  26. Glycolysis • Glycolysis: a series of 10 enzyme-catalyzed reactions by which glucose is oxidized to two molecules of pyruvate • glycolysis is a 4-electron oxidation; it occurs in two separate 2-electron oxidation steps

  27. Glycolysis - Rexn 1 • Reaction 1: phosphorylation of a-D-glucose

  28. Glycolysis - Rexn 2 • Reaction 2: isomerization of glucose 6-phosphate to fructose 6-phosphate

  29. Glycolysis - Rexn 2 • this isomerization is most easily seen by considering the open-chain forms of each monosaccharide • it is one keto-enol tautomerism followed by another

  30. Glycolysis - Rexn 3 • Reaction 3: phosphorylation of fructose 6-phosphate

  31. Glycolysis - Rexn 4 • Reaction 4: cleavage of fructose 1,6-bisphosphate to two triose phosphates

  32. Glycolysis - Rexn 4 • reaction 4 is a reverse aldol reaction • an 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

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

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

  35. Glycolysis - Rexn 5 • Reaction 5: isomerization of triose phosphates

  36. Glycolysis - Rexn 6 • Reaction 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, NAD+, is reduced to NADH

  37. Glycolysis - Rexn 6 • We divide this reaction into three steps • step 1: formation of a thiohemiacetal

  38. Glycolysis - Rexn 6 • step 2: oxidation of the thiohemiacetal by NAD+

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

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

  41. Glycolysis - Rexn 8 • Reaction 8: isomerization of 3-phosphoglycerate to 2-phosphoglycerate

  42. Glycolysis - Rexn 9 • Reaction 9: dehydration of 2-phosphoglycerate

  43. Glycolysis - Rexn 10 • Reaction 10: phosphate transfer to ADP • stage 1: transfer of the phosphate group

  44. Glycolysis - Rexn 10 • stage 2: enolization to pyruvate

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

  46. 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

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

  48. 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

  49. 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

  50. 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

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