1. © 2011 Pearson Education, Inc. 1 Organic Chemistry 6 th Edition Paula Yurkanis Bruice Chapter 25 The Organic Chemistry of the Coenzymes, Compounds Derived from Vitamins

2. © 2011 Pearson Education, Inc. 2 Many enzymes catalyze a reaction with the help of a cofactor. Cofactors can be metal ions or organic molecules. An enzyme that has a tightly bound metal ion is called a metalloenzyme. Cofactors that are organic molecules are coenzymes. Coenzymes are derived from vitamins.

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4. 4 The Pyridine Nucleotide Coenzyme Is Needed for Many Redox Reactions NAD(P) + are oxidizing agents. NAD(P)H are reducing agents.

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6. 6 NAD + is composed of two nucleotides linked together through their phosphate groups The adenine nucleotide portion of NAD + is derived from ATP

7. © 2011 Pearson Education, Inc. 7 Many enzymes that catalyze oxidation reactions are called dehydrogenase: NAD + and NADH are catabolic coenzymes, whereas NADP + and NADPH are anabolic coenzymes

8. © 2011 Pearson Education, Inc. 8 Mechanisms for the pyridine nucleotide coenzymes: All the chemistry of the pyridine nucleotide coenzymes takes place at the 4-position of the pyridine ring

9. © 2011 Pearson Education, Inc. 9 Glyceraldehyde-3-phosphate dehydrogenase uses NAD + as an oxidizing coenzyme:

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11. © 2011 Pearson Education, Inc. 11 The mechanism for reduction by NAD or by NADPH: NADH and NADPH are hydride donors

12. © 2011 Pearson Education, Inc. 12 The structural complexity of a coenzyme is needed for enzyme recognition. Molecular recognition allows the enzyme to bind the substrate and the coenzyme in the proper orientation for reaction. Biological redox reactions are equilibrium reactions driven in the appropriate direction by the removal of reaction products.

13. © 2011 Pearson Education, Inc. 13 A Biological Redox Reaction Is Highly Selective

14. © 2011 Pearson Education, Inc. 14 A reducing enzyme can distinguish between the two hydrogens at the 4-position of the nicotinamide ring:

15. © 2011 Pearson Education, Inc. 15 FAD and FMN are coenzymes used to oxidize substrates A flavoprotein is an enzyme that contains either FAD or FMN

16. © 2011 Pearson Education, Inc. 16 The structure of the oxidized FMN cofactor:

17. © 2011 Pearson Education, Inc. 17 Biological Redox Reactions Involving FAD or FMN

18. © 2011 Pearson Education, Inc. 18 FAD and FMN are oxidizing agents, whereas FADH 2 and FMNH 2 are reducing agents:

19. © 2011 Pearson Education, Inc. 19 Mechanism for dihydrolipoyl dehydrogenase: Thiolate addition to 4a  position Two-electron transfer to the flavin ring

20. © 2011 Pearson Education, Inc. 20 Mechanism for D- or L-amino acid oxidase:

21. © 2011 Pearson Education, Inc. 21 Unlike NAD + and NADH, FAD and FADH 2 do not dissociate from the enzyme: But NAD + is required to reoxidize the reduced cofactor

22. © 2011 Pearson Education, Inc. 22 Thiamine pyrophosphate (TPP) is the coenzyme required by enzymes that catalyze the transfer of a two- carbon fragment:

23. © 2011 Pearson Education, Inc. 23 The enzyme pyruvate decarboxylase requires thiamine pyrophosphate (TTP) as a coenzyme: TTP affords a nucleophilic ylide carbanion that facilitates decarboxylation:

24. © 2011 Pearson Education, Inc. 24 Mechanism for pyruvate decarboxylase: Enamine intermediate

25. © 2011 Pearson Education, Inc. 25 The conversion of pyruvate to acetyl-CoA requires coenzymes TPP, lipoate, coenzyme A, FAD, and NAD +

26. © 2011 Pearson Education, Inc. 26 Mechanism for acetyl-CoA formation:

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28. © 2011 Pearson Education, Inc. 28 Biotin is required by enzymes that catalyze the carboxylation of a carbon adjacent to a carbonyl group:

29. © 2011 Pearson Education, Inc. 29 Enzymatic reactions utilizing the biotin coenzyme:

30. © 2011 Pearson Education, Inc. 30 In addition to requiring bicarbonate, biotin-requiring enzymes require Mg 2+ and ATP:

31. © 2011 Pearson Education, Inc. 31 Mechanism for carboxylation of acetyl-CoA by acetyl- CoA carboxylase:

32. © 2011 Pearson Education, Inc. 32 Pyridoxal phosphate (PLP) is required by enzymes that catalyze certain transformations of amino acids:

33. © 2011 Pearson Education, Inc. 33 Amino Acid Transformations That Require PLP Coenzyme

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36. © 2011 Pearson Education, Inc. 36 The first step of the reactions involves the breakage of the bond attached to C 

37. © 2011 Pearson Education, Inc. 37 Mechanism for transimination:

38. © 2011 Pearson Education, Inc. 38 Mechanism for PLP-catalyzed decarboxylation of an amino acid:

39. © 2011 Pearson Education, Inc. 39 Mechanism for PLP-catalyzed racemization of an L- amino acid:

40. © 2011 Pearson Education, Inc. 40 Mechanism for PLP-catalyzed transamination of an amino acid:

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42. © 2011 Pearson Education, Inc. 42 Mechanism for PLP-catalyzed C  —C  bond cleavage:

43. © 2011 Pearson Education, Inc. 43 The bond cleaved in the first step depends on the conformation of the enzyme-bound amino acid

44. © 2011 Pearson Education, Inc. 44 Enzymes that catalyze certain rearrangement reactions require coenzyme B 12

45. © 2011 Pearson Education, Inc. 45 Enzymatic Reactions Requiring B 12

46. © 2011 Pearson Education, Inc. 46 In a coenzyme B 12 –requiring reaction, a group (Y) bonded to one carbon changes places with a hydrogen bonded to an adjacent carbon:

47. © 2011 Pearson Education, Inc. 47 Mechanism for a coenzyme B 12 –requiring enzyme-catalyzed reaction:

48. © 2011 Pearson Education, Inc. 48 Tetrahydrofolate (THF) is the coenzyme required for one-carbon transfer reactions:

49. © 2011 Pearson Education, Inc. 49 The Six Different THF-Coenzymes

50. © 2011 Pearson Education, Inc. 50 GAR transformylase is an example of an enzyme that requires a THF-coenzyme:

51. © 2011 Pearson Education, Inc. 51 The Enzyme That Converts U into T

52. © 2011 Pearson Education, Inc. 52 Mechanism for the reaction catalyzed by thymidylate synthase:

53. © 2011 Pearson Education, Inc. 53 Conversion of Dihydrofolate Back to N 5, N 10 -Methylene-THF

54. © 2011 Pearson Education, Inc. 54 5-Fluorouracil is a mechanism-based inhibitor or suicide inhibitor of thymidylate synthase used in cancer chemotherapy

55. © 2011 Pearson Education, Inc. 55 Aminopterin and methotrexate competitively inhibit dihydrofolate reductase and are used as anticancer drugs

56. © 2011 Pearson Education, Inc. 56 Vitamin K is required for proper clotting of blood

57. © 2011 Pearson Education, Inc. 57 Vitamin KH 2 is required by the enzyme that catalyzes the carboxylation of the  -carbon of a glutamate side chain

58. © 2011 Pearson Education, Inc. 58 Mechanism for the vitamin KH 2 –dependent carboxylation of glutamate Dioxetane formation:

59. © 2011 Pearson Education, Inc. 59 Carboxylation mediated by vitamin K base: Dioxetane intermediate

60. © 2011 Pearson Education, Inc. 60 Regeneration of Vitamin KH 2