1. Lecture 25 Chemical Sense in Metabolism

2. Making and Breaking C–C Bonds Homolytic reactions Heterolytic reactions

3. Making and Breaking C–C Bonds Nucleophilic substitutions

4. Nucleophilic Substitution Reactions S N 1

5. Carbocation

6. Common Biological Nucleophiles

7. S N 2 Nucleophilic Substitution –– ––

8. Reactivity is S N 2 Reactions

9. Leaving Group Must accommodate a pair of electrons –And sometimes a negative charge

10. Major Role of Phosphorylation Converts a poor leaving group ( – OH) into a good one (P i, PP i )

11. Acid Catalysis of Substitution Reactions This H is often donated by an acidic sidechain of enzyme

12. Central Importance of Carbonyls 1. Can produce a carbocation 2. Can stabilize a carbanion

13. Biological Carbonyls

14. Aldol Condensation

17. Aldolase Reaction Glycolysis and gluconeogenesis

18. Claisen Condensation

20. Thioesters in Biology In thioesters, the carbonyl carbon has more positive character than carbonyl carbon in oxygen ester.

21. “High-Energy” Thioester Compounds

22. Coenzyme A

23. Fatty Acid Metabolism Uses Claisen condensation Thiolase acts in fatty acid oxidation for energy production

24. Thiolase: Role of Cys-SH

26. Energy Diagram for Reaction ‡ is the transition state –Pentacovalent carbon, for example

27. Functional Groups on Enzymes Amino acid side chains – –Imidazole –

28. Functional Groups on Enzymes Coenzymes/cofactors –Pyridoxal phosphate Metal ions and complexes – Mg 2+, Mn 2+, Co 2+, Fe 2+, Zn 2+, Cu 2+, Mo 3+

29. Enzyme Inhibitors and Poisons Chelating agents –EDTA (divalent cations) –CN – (Fe 2+ ) Cofactor analogs –Warfarin Suicide substrates

30. Lecture 26 ATP and Phosphoryl Group Transfers

31. Phosphate Esters and Anhydrides

32. Phosphoryl Group Transfers

33. Phosphoryl (Not Phosphate) Transfers

34. Nucleophilic Displacements

35. ATP as a Phophoryl Donor 2 roles for ATP –Thermodynamic Drive unfavorable reactions –Mechanistic Offer 3 electrophilic phosphorous atoms for nucleophilic attack

36. ATP as Phosphoryl Donor 3 points of nucleophilic attack

37. Adenylyation: Attack on  -P

38. Adenylation: Attack on  -P

39. Pyrophosphorylation: Attack on  -P

40. Phosphorylation: Attack on  -P

41. Amino Acid Sidechains as Nucleophiles

42. Enzymatic Phosphoryl Transfers Four classes –Phosphatases Water is acceptor/nucleophile –Phosphodiesterases Water is acceptor/nucleophile –Kinases Nucleophile is not water –Phosphorylases Phosphate is nucleophile

43. Phosphatases: Glucose-6- Phosphatase

44. Phosphatases: Glucose-6- Phosphate

45. Phosphodiesterases: RNAase

47. Kinases:  -Phosphoryl Transfer Transfer from ATP

48. Kinases: P-Enzyme Intermediates

50. Kinases

51. Pyruvate Kinase Makes ATP (∆Gº= –31 kJ/mol) from PEP ∆Gº= –62 kJ/mol

52. Phosphoryl-Group Transfer Potential

53. Significance of “High-Energy” P Compounds Drive synthesis of compounds below Phosphated compounds are more reactive –Thermodynamically –Kinetically If organism has ATP (etc…), it can do work and resist entropy  Cells must get ATP