1. Functions of nucleotides in biochemistry ● Building blocks of nucleic acids ● Cosubstrates and coenzymes ● Signaling

2. Structures of NAD, acetyl-CoA, and PAPS © Michael Palmer 2014

3. The RNA world hypothesis © Michael Palmer 2014

4. Why have cosubstrates become fossilized, whereas enzymes have not? © Michael Palmer 2014

5. Metabolic routes and pathways of nucleotides ● De novo synthesis ● Intestinal uptake of nucleosides ● Endogenous turnover (partial degradation/salvage) ● Degradation and excretion

6. Overview of purine synthesis © Michael Palmer 2014

7. IMP synthesis (1) © Michael Palmer 2014

8. IMP synthesis (2) © Michael Palmer 2014

9. IMP synthesis (3) © Michael Palmer 2014

10. A bifunctional enzyme combines AIR carboxylase and SAICAR synthetase activities © Michael Palmer 2014

11. Synthesis of AMP from IMP © Michael Palmer 2014

12. Synthesis of GMP from IMP © Michael Palmer 2014

13. Feedback regulation in purine synthesis © Michael Palmer 2014

14. Overview of digestion and utilization of nucleic acids © Michael Palmer 2014

15. Utilization of ribose and deoxyribose © Michael Palmer 2014

16. Degradation of endogenous purine nucleotides (overview) © Michael Palmer 2014

17. Adenine nucleotide degradation © Michael Palmer 2014

18. The guanase and xanthine dehydrogenase/oxidase reactions © Michael Palmer 2014

19. Renal urate elimination: tubular reuptake and secretion © Michael Palmer 2014

20. Non-primates break down uric acid to allantoin © Michael Palmer 2014

21. Overview of purine salvage reactions © Michael Palmer 2014

22. Enzyme defects in purine degradation and salvage © Michael Palmer 2014

23. Gout ● Genetic or dietary factors cause chronically increased urate production or retention ● Urate has limited solubility and may form crystalline deposits, preferentially in joints and soft tissue ● Urate crystals activate inflammation and lead to arthritis that is painful and, in the long run, destructive

24. Diets and drugs that may promote gout ● too much food, too rich in purines ● excessive fructose or sucrose ● alcoholic beverages—but not all kinds: beer yes, wine no ● anorexia nervosa (!) ● drugs that interfere with uric acid secretion: pyrazinamide, salicylic acid ● drugs that contain purines: dideoxyadenosine

25. Gout: the fructose connection © Michael Palmer 2014

26. Drugs that affect purine degradation and elimination © Michael Palmer 2014

27. Acute urate nephropathy in tumor lysis syndrome ● Occurs during chemotherapy of malignancies, particularly with lymphomas and leukemias ● Chemotherapy causes acute decay of large numbers of tumor cells ● Degradation of nucleic acids from decaying cells produces large amounts of uric acid ● Uric acid in nascent urine exceeds solubility and precipitates, clogging up and damaging the kidney tubules ● Clinically manifest as acute kidney failure with high fatality rate

28. Rasburicase, a better preventive treatment for urate nephropathy © Michael Palmer 2014

29. Synthesis of pyrimidines (1) © Michael Palmer 2014

30. Synthesis of pyrimidines (2) © Michael Palmer 2014

31. Degradation of pyrimidines © Michael Palmer 2014

32. β-Alanine may be used to synthesize carnosine © Michael Palmer 2014

33. Synthesis of deoxyribonucleotides © Michael Palmer 2014

34. The thymidylate synthase reaction © Michael Palmer 2014

35. Nucleotide antimetabolites as anticancer and antiviral drugs © Michael Palmer 2014

36. Dual action mode of 5-fluorouracil © Michael Palmer 2014

37. Inhibition of thymidylate synthase by 5-fluorouracil © Michael Palmer 2014

38. Mutagenesis through mispairing of the 5-FU iminol tautomer © Michael Palmer 2014

39. Thymine and various halogen analogues © Michael Palmer 2014

40. Indirect inhibition of thymidine synthesis by methotrexate © Michael Palmer 2014

41. Mercaptopurine inhibits purine synthesis © Michael Palmer 2014

42. Structure of cytosine arabinoside (araC) © Michael Palmer 2014

43. Metabolic activation and inactivation of araC © Michael Palmer 2014

44. Overexpression of 5′-nucleotidase in leukemic cells reduces survival rates © Michael Palmer 2014

45. Action mode of araCTP © Michael Palmer 2014

46. Dideoxyadenosine inhibits retroviral DNA polymerase © Michael Palmer 2014

47. Aciclovir and ganciclovir © Michael Palmer 2014

48. Aciclovir: mode of action on herpes virus © Michael Palmer 2014

49. Some more inhibitors of viral nucleic acid synthesis © Michael Palmer 2014